Novel inhibitors

ABSTRACT

The invention relates to a compound of formula (I): A-B-D-E (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein: A is selected from monocyclic and bicyclic heteroaryl, which may independently substituted by alkyl or amino; B is selected from alkyl, heteroalkyl, alkyl-amino, aryl, heteroaryl, cycloalkyl, heterocyclyl and alkylene, wherein said groups may independently be substituted by alkyl; D is selected from aryl-amino, heteroaryl-amino, cycloalkyl-amino, heterocyclyl, heterocyclyl-amino, urea, thioamide, thiourea, sulfonamide, sulfoximine and sulfamoyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups may independently be substituted; and E is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups may independently be substituted. The compounds of formula (I) are inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water.

FIELD OF THE INVENTION

The invention relates to novel heterocyclic derivatives as inhibitors ofglutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecularcyclization of N-terminal glutamine residues into pyroglutamic acid(5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecularcyclization of N-terminal glutamate residues into pyroglutamic acidunder liberation of water.

BACKGROUND OF THE INVENTION

Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecularcyclization of N-terminal glutamine residues into pyroglutamic acid(pGlu*) liberating ammonia. A QC was first isolated by Messer from thelatex of the tropical plant Carica papaya in 1963 (Messer, M. 1963Nature 4874, 1299). 24 years later, a corresponding enzymatic activitywas discovered in animal pituitary (Busby, W. H. J. et al. 1987 J BiolChem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 Proc Natl AcadSci USA 84, 3628-3632). For the mammalian QC, the conversion of Gln intopGlu by QC could be shown for the precursors of TRH and GnRH (Busby, W.H. J. et al. 1987 J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess,J. 1987 Proc Natl Acad Sci USA 84, 3628-3632). In addition, initiallocalization experiments of QC revealed a co-localization with itsputative products of catalysis in bovine pituitary, further improvingthe suggested function in peptide hormone synthesis (Bockers, T. M. etal. 1995 J Neuroendocrinol 7, 445-453). In contrast, the physiologicalfunction of the plant QC is less clear. In the case of the enzyme fromC. papaya, a role in the plant defense against pathogenic microorganismswas suggested (El Moussaoui, A. et al. 2001 Cell Mol Life Sci 58,556-570). Putative QCs from other plants were identified by sequencecomparisons recently (Dahl, S. W. et al. 2000 Protein Expr Purif 20,27-36). The physiological function of these enzymes, however, is stillambiguous.

The QCs known from plants and animals show a strict specificity forL-Glutamine in the N-terminal position of the substrates and theirkinetic behavior was found to obey the Michaelis-Menten equation (Pohl,T. et al. 1991 Proc Natl Acad Sci USA 88, 10059-10063; Consalvo, A. P.et al. 1988 Anal Biochem 175, 131-138; Gololobov, M. Y. et al. 1996 BiolChem Hoppe Seyler 377, 395-398). A comparison of the primary structuresof the QCs from C. papaya and that of the highly conserved QC frommammals, however, did not reveal any sequence homology (Dahl, S. W. etal. 2000 Protein Expr Purif 20, 27-36). Whereas the plant QCs appear tobelong to a new enzyme family (Dahl, S. W. et al. 2000 Protein ExprPurif 20, 27-36), the mammalian QCs were found to have a pronouncedsequence homology to bacterial aminopeptidases (Bateman, R. C. et al.2001 Biochemistry 40, 11246-11250), leading to the conclusion that theQCs from plants and animals have different evolutionary origins.

Recently, it was shown that recombinant human QC as well as QC-activityfrom brain extracts catalyze both, the N-terminal glutaminyl as well asglutamate cyclization. Most striking is the finding, thatcyclase-catalyzed Glu₁-conversion is favored around pH 6.0 whileGln₁-conversion to pGlu-derivatives occurs with a pH-optimum of around8.0. Since the formation of pGlu-Aβ-related peptides can be suppressedby inhibition of recombinant human QC and QC-activity from pig pituitaryextracts, the enzyme QC is a target in drug development for treatment ofAlzheimer's disease.

Inhibitors of QC are e.g. described in WO 2004/098625, WO 2004/098591,WO 2005/039548, WO 2005/075436, WO 2008/055945, WO 2008/055947, WO2008/055950, WO2008/065141, WO 2008/110523, WO 2008/128981, WO2008/128982, WO 2008/128983, WO 2008/128984, WO 2008/128985, WO2008/128986, WO 2008/128987, WO 2010/026212, WO 2011/029920, WO2011/107530, WO 2011/110613, WO 2011/131748 and WO 2012/123563.

EP 02 011 349.4 discloses polynucleotides encoding insect glutaminylcyclase, as well as polypeptides encoded thereby and their use inmethods of screening for agents that reduce glutaminyl cyclase activity.Such agents are useful as pesticides.

Definitions

The terms “k_(i)” or “K_(I)” and “K_(D)” are binding constants, whichdescribe the binding of an inhibitor to and the subsequent release froman enzyme. Another measure is the “IC₅₀” value, which reflects theinhibitor concentration, which at a given substrate concentrationresults in 50% enzyme activity.

The term “DP IV-inhibitor” or “dipeptidyl peptidase IV inhibitor” isgenerally known to a person skilled in the art and means enzymeinhibitors, which inhibit the catalytic activity of DP IV or DP IV-likeenzymes.

“DP IV-activity” is defined as the catalytic activity of dipeptidylpeptidase IV (DP IV) and DP IV-like enzymes. These enzymes arepost-proline (to a lesser extent post-alanine, post-serine orpost-glycine) cleaving serine proteases found in various tissues of thebody of a mammal including kidney, liver, and intestine, where theyremove dipeptides from the N-terminus of biologically active peptideswith a high specificity when proline or alanine form the residues thatare adjacent to the N-terminal amino acid in their sequence.

The term “PEP-inhibitor” or “prolyl endopeptidase inhibitor” isgenerally known to a person skilled in the art and means enzymeinhibitors, which inhibit the catalytic activity of prolyl endopeptidase(PEP, prolyl oligopeptidase, POP).

“PEP-activity” is defined as the catalytic activity of an endoproteasethat is capable to hydrolyze post proline bonds in peptides or proteinswhere the proline is in amino acid position 3 or higher counted from theN-terminus of a peptide or protein substrate.

The term “QC” as used herein comprises glutaminyl cyclase (QC) andQC-like enzymes. QC and QC-like enzymes have identical or similarenzymatic activity, further defined as QC activity. In this regard,QC-like enzymes can fundamentally differ in their molecular structurefrom QC.

Examples of QC-like enzymes are the glutaminyl-peptidecyclotransferase-like proteins (QPCTLs) from human (GenBank NM)_017659),mouse (GenBank BC058181), Macaca fascicularis (GenBank AB168255), Macacamulatta (GenBank XM_001110995), Canis familiaris (GenBank XM_541552),Rattus norvegicus (GenBank XM_001066591), Mus musculus (GenBankBC058181) and Bos taurus (GenBank BT026254).

The term “QC activity” as used herein is defined as intramolecularcyclization of N-terminal glutamine residues into pyroglutamic acid(pGlu*) or of N-terminal L-homoglutamine or L-β-homoglutamine to acyclic pyro-homoglutamine derivative under liberation of ammonia. Seetherefore schemes 1 and 2.

The term “EC” as used herein comprises the activity of QC and QC-likeenzymes as glutamate cyclase (EC), further defined as EC activity.

The term “EC activity” as used herein is defined as intramolecularcyclization of N-terminal glutamate residues into pyroglutamic acid(pGlu*) by QC. See therefore scheme 3.

The term “QC-inhibitor” “glutaminyl cyclase inhibitor” is generallyknown to a person skilled in the art and means enzyme inhibitors, whichinhibit the catalytic activity of glutaminyl cyclase (QC) or itsglutamyl cyclase (EC) activity.

Potency of QC Inhibition

In light of the correlation with QC inhibition, in preferredembodiments, the subject method and medical use utilize an agent with anIC₅₀ for QC inhibition of 10 μNA or less, more preferably of 1 μNA orless, even more preferably of 0.1 μNA or less or 0.01 μNA or less, ormost preferably 0.001 μNA or less. Indeed, inhibitors with K_(i) valuesin the lower micromolar, preferably the nanomolar and even morepreferably the picomolar range are contemplated. Thus, while the activeagents are described herein, for convenience, as “QC inhibitors”, itwill be understood that such nomenclature is not intending to limit thesubject of the invention to a particular mechanism of action.

Molecular Weight of QC Inhibitors

In general, the QC inhibitors of the subject method or medical use willbe small molecules, e.g., with molecular weights of 500 g/mole or less,400 g/mole or less, preferably of 350 g/mole or less, and even morepreferably of 300 g/mole or less and even of 250 g/mole or less.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanbeing sought by a researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disease ordisorder being treated.

As used herein, the term “pharmaceutically acceptable” embraces bothhuman and veterinary use: For example the term “pharmaceuticallyacceptable” embraces a veterinarily acceptable compound or a compoundacceptable in human medicine and health care.

Throughout the description and the claims the expression “alkyl”, unlessspecifically limited, denotes a C₁₋₁₂ alkyl group, suitably a C₁₋₈ alkylgroup, e.g. C₁₋₆ alkyl group, e.g. C₁₋₄ alkyl group. Alkyl groups may bestraight chain or branched. Suitable alkyl groups include, for example,methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g.n-butyl, iso-butyl, sec-butyl and tert-butyl), pentyl (e.g. n-pentyl),hexyl (e.g. n-hexyl), heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl).The expression “alk”, for example in the expressions “alkoxy”,“haloalkyl” and “thioalkyl” should be interpreted in accordance with thedefinition of “alkyl”. Exemplary alkoxy groups include methoxy, ethoxy,propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g.n-pentoxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy(e.g. n-octoxy). Exemplary thioalkyl groups include methylthio-.Exemplary haloalkyl groups include fluoroalkyl e.g. CF₃.

The expression “alkylene” denotes a chain of formula —(CH₂)_(n)— whereinn is an integer e.g. 1-5, unless specifically limited.

The expression “cycloalkyl”, unless specifically limited, denotes aC₃₋₁₀ cycloalkyl group (i.e. 3 to 10 ring carbon atoms), more suitably aC₃₋₈ cycloalkyl group, e.g. a C₃₋₆ cycloalkyl group. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. A most suitable number of ringcarbon atoms is three to six.

The expression “heterocyclyl”, unless specifically limited, refers to acarbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms arereplaced by heteroatoms selected from N, S and O. A specific example ofa heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or moreparticularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3,particularly 1 or 2, especially 1) ring atoms are replaced byheteroatoms selected from N, S or O. Exemplary heterocyclyl groupscontaining one hetero atom include pyrrolidine, tetrahydrofuran andpiperidine, and exemplary heterocyclyl groups containing two heteroatoms include morpholine, piperazine, dioxolane and dioxane. A furtherspecific example of a heterocyclyl group is a cycloalkenyl group (e.g. acyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1or 2, especially 1) ring atoms are replaced by heteroatoms selected fromN, S and O. An example of such a group is dihydropyranyl (e.g.3,4-dihydro-2H-pyran-2-yl-).

The expression “aryl”, unless specifically limited, denotes a C_(6_12)aryl group, suitably a C₆₋₁₀ aryl group, more suitably a C₆₋₈ arylgroup. Aryl groups will contain at least one aromatic ring (e.g. one,two or three rings). An example of a typical aryl group with onearomatic ring is phenyl. An example of a typical aryl group with twoaromatic rings is naphthyl.

The expression “heteroaryl”, unless specifically limited, denotes anaryl residue, wherein one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or3) ring atoms are replaced by heteroatoms selected from N, S and O, orelse a 5-membered aromatic ring containing one or more (e.g. 1, 2, 3, or4, suitably 1, 2 or 3) ring atoms selected from N, S and O. Exemplarymonocyclic heteroaryl groups having one heteroatom include: fivemembered rings (e.g. pyrrole, furan, thiophene); and six membered rings(e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl).Exemplary monocyclic heteroaryl groups having two heteroatoms include:five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole,isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-ylimidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine,pyrazine). Exemplary monocyclic heteroaryl groups having threeheteroatoms include: 1,2,3-triazole and 1,2,4-triazole. Exemplarymonocyclic heteroaryl groups having four heteroatoms include tetrazole.Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl),benzofuran, benzthiophene, quinoline, isoquinoline, indazole,benzimidazole, benzthiazole, quinazoline and purine.

The expression “-alkylaryl”, unless specifically limited, denotes anaryl residue which is connected via an alkylene moiety e.g. a C₁₋₄alkylene moiety.

The expression “-alkylheteroaryl”, unless specifically limited, denotesa heteroaryl residue which is connected via an alkylene moiety e.g. aC₁₋₄ alkylene moiety.

The term “halogen” or “halo” comprises fluorine (F), chlorine (Cl) andbromine (Br).

The term “amino” refers to the group —NH₂.

When benzimidazolyl is shown as benzimidazol-5-yl, which is representedas:

the person skilled in the art will appreciate that benzimidazol-6-yl,which is represented as:

is an equivalent structure. As employed herein, the two forms ofbenzimidazolyl are covered by the term “benzimidazol-5-yl”.

Stereoisomers:

All possible stereoisomers of the claimed compounds are included in thepresent invention.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Preparation and Isolation of Stereoisomers:

Where the processes for the preparation of the compounds according tothe invention give rise to a mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Pharmaceutically Acceptable Salts:

In view of the close relationship between the free compounds and thecompounds in the form of their salts or solvates, whenever a compound isreferred to in this context, a corresponding salt, solvate or polymorphis also intended, provided such is possible or appropriate under thecircumstances.

Salts and solvates of the compounds of formula (I) and physiologicallyfunctional derivatives thereof which are suitable for use in medicineare those wherein the counter-ion or associated solvent ispharmaceutically acceptable. However, salts and solvates havingnon-pharmaceutically acceptable counter-ions or associated solvents arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds and theirpharmaceutically acceptable salts and solvates.

Suitable salts according to the invention include those formed with bothorganic and inorganic acids or bases. Pharmaceutically acceptable acidaddition salts include those formed from hydrochloric, hydrobromic,sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic,oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic,oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for examplep-toluenesulfonic, benzenesulfonic, naphthalenesulfonic ornaphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic,cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy orhalo substituted cinnamic, including 4-methyl and 4-methoxycinnamicacid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or3-hydroxy-2-naphthoic), naphthaleneacrylic (for examplenaphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (forexample 1,4-benzenediacrylic), isethionic acids, perchloric, propionic,glycolic, hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic,saccharinic and trifluoroacetic acid. Pharmaceutically acceptable basesalts include ammonium salts, alkali metal salts such as those of sodiumand potassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine.

All pharmaceutically acceptable acid addition salt forms of thecompounds of the present invention are intended to be embraced by thescope of this invention.

Polymorph Crystal Forms:

Furthermore, some of the crystalline forms of the compounds may exist aspolymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e. hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention. Thecompounds, including their salts, can also be obtained in the form oftheir hydrates, or include other solvents used for theircrystallization.

Prodrugs:

The present invention further includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the desired therapeutically active compound. Thus, in thesecases, the methods of treatment of the present invention, the term“administering” shall encompass the treatment of the various disordersdescribed with prodrug versions of one or more of the claimed compounds,but which converts to the above specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Protective Groups:

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991, fully incorporatedherein by reference. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

As used herein, the term “composition” is intended to encompass aproduct comprising the claimed compounds in the therapeuticallyeffective amounts, as well as any product which results, directly orindirectly, from combinations of the claimed compounds.

Carriers and Additives for Galenic Formulations:

Thus, for liquid oral preparations, such as for example, suspensions,elixirs and solutions, suitable carriers and additives mayadvantageously include water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like; for solid oral preparationssuch as, for example, powders, capsules, gelcaps and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like.

Carriers, which can be added to the mixture, include necessary and inertpharmaceutical excipients, including, but not limited to, suitablebinders, suspending agents, lubricants, flavorants, sweeteners,preservatives, coatings, disintegrating agents, dyes and coloringagents.

Soluble polymers as targetable drug carriers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolyllysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, polyacticacid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Suitable binders include, without limitation, starch, gelatin, naturalsugars such as glucose or betalactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth or sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like.

Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

DESCRIPTION OF THE INVENTION

According to the invention there is provided a compound of formula (I):

A-B-D-E  (I)

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof, wherein:

-   -   A is selected from monocyclic and bicyclic heteroaryl, which may        independently substituted by alkyl or amino;    -   B is selected from alkyl, heteroalkyl, alkyl-amino, aryl,        heteroaryl, cycloalkyl, heterocyclyl and alkylene, wherein said        groups may independently be substituted by alkyl;    -   D is selected from aryl-amino, heteroaryl-amino,        cycloalkyl-amino, heterocyclyl, heterocyclyl-amino, urea,        thioamide, thiourea, sulfonamide and sulfoximine, wherein said        aryl, heteroaryl, cycloalkyl and heterocyclyl groups may        independently be substituted with one or more substituents;    -   In another embodiment, D is sulfamoyl;    -   E is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl,        wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl        groups may independently be substituted with one or more        substituents.

In a preferred embodiment, there is provided a compound of formula (I)with the provisos that

-   -   i) when B is alkyl or heteroalkyl, then D may not be        sulfonamide; and    -   ii) the compound of formula (I) is not a compound selected from:

Compounds of proviso i) are known from the CAS Registry Database withoutany functional definition and are selected from

Compound Chemical Name CAS No. A Benzenesulfonamide,N-[3-(5-amino-1,3,4-thiadiazol-2- 1211493-15-0 yl)propyl]-4-chloro- BBenzenesulfonamide, N-[3-(5-amino-1,3,4-thiadiazol-2- 1211465-90-5yl)propyl]-4-bromo- C Benzenesulfonamide,N-[3-(5-amino-1,3,4-thiadiazol-2- 1199216-00-6 yl)propyl]-4-methyl- DBenzenesulfonamide, 4-(1,1-dimethylethyl)-N-[3-(4- 2128710-23-4methyl-4H-1,2,4-triazol-3-yl)propyl]- E Benzenesulfonamide,N-[3-(5-amino-1,3,4-thiadiazol-2- 1211492-68-0 yl)propyl]-4-fluoro- FBenzenesulfonamide, N-[3-(5-amino-1,3,4-thiadiazol-2- 1211492-61-3yl)propyl]-4-methoxy- G Benzenesulfonamide,N-[2-[(5-amino-1,3,4-thiadiazol-2- 694497-92-2 yl)thio]ethyl]-4-methyl-H Benzenesulfonamide, 4-methyl-N-[2-[(4-methyl-4H- 329266-08-21,2,4-triazol-3-yl)thio]ethyl]- (CA INDEX NAME) I Benzenesulfonamide,N-(1H-benzimidazol-6-ylmethyl)- 1798221-00-7 4-(1-methylethoxy)- JBenzenesulfonamide, N-(1H-benzimidazol-6-ylmethyl)- 1798220-92-44-chloro- K Benzenesulfonamide, N-(1H-benzimidazol-6-ylmethyl)-1798183-20-6 4-ethoxy- L Benzenesulfonamide,N-(1H-benzimidazol-6-ylmethyl)- 1798182-87-2 4-fluoro-3-methyl- MBenzenesulfonamide, N-(1H-benzimidazol-6-ylmethyl)- 1795649-47-64-(1,1-dimethylethyl)- N Benzenesulfonamide,N-(1H-benzimidazol-6-ylmethyl)- 1795648-73-5 4-(1-methylethyl)- OBenzenesulfonamide, N-(1H-benzimidazol-6-ylmethyl)- 1795648-65-54-ethyl- P Benzenesulfonamide, N-(1H-benzimidazol-6-ylmethyl)-1795648-57-5 3,4-dimethyl- Q Benzenesulfonamide,N-(1H-benzimidazol-6-ylmethyl)- 1795648-51-9 4-methyl- RBenzenesulfonamide, N-(1H-benzimidazol-6-ylmethyl)- 1795588-58-74-fluoro- S Benzenesulfonamide, N-(1H-benzimidazol-6-ylmethyl)-1790918-17-0 3,4-dimethoxy- T Benzenesulfonamide,N-(1H-benzimidazol-6-ylmethyl)- 1790918-11-4 4-methoxy-3-methyl- UBenzenesulfonamide, N-(1H-benzimidazol-6-ylmethyl)- 1787494-28-34-methoxy-

In a preferred embodiment according tp proviso i), the compound offormula (I) is not a compound selected from compounds A to U.

Compound V of proviso ii) is known from CAS Registry with CAS No.2117405-13-5 without functional definition. Compound W of proviso ii) isknown from CAS Registry with CAS No. 1090606-68-0 without functionaldefinition. Compound W of proviso ii) is known from CAS Registry withCAS No. 2093539-54-7 without functional definition.

When A is a monocyclic heteroaryl, A is preferably selected fromthiadiazolyl, such as 1,3,4-thiadiazolyl, thiazolyl and triazolyl, suchas 1,2,4-triazolyl. In one embodiment of the invention, said monocyclicheteroaryl is substituted by amino or methyl. In another embodiment,said monocyclic heteroaryl is unsubstituted.

When cycloalkyl and heterocyclyl are substituted, they are typicallysubstituted by 1 or 2 substituents (e.g. 1 substituent). Typically thesubstituent is C₁₋₆ alkyl (i.e. methyl) or halogen (i.e. chlorine orfluorine). More typically cycloalkyl and heterocyclyl groups areunsubstituted.

When aryl and heteroaryl are substituted, they are typically substitutedby 1, 2 or 3 (e.g. 1 or 2) substituents. Substituents for aryl andheteroaryl are selected from C₁₋₆ alkyl (e.g. methyl), C₂₋₆ alkenyl(e.g. buten-3-yl), C₂₋₆ alkynyl (e.g. butyn-3-yl), C₁₋₆ haloalkyl (e.g.fluoromethyl, trifluoromethyl), —C₁₋₆ thioalkyl (e.g. —S-methyl),—SOC₁₋₄ alkyl (e.g. —SOmethyl), —SO₂C₁₋₄ alkyl (e.g. —SO₂methyl), C₁₋₆alkoxy- (e.g. methoxy, ethoxy), —O—C₃₋₈ cycloalkyl (e.g. —O-cyclopentylor —O-cyclohexyl), C₃₋₈ cycloalkyl (e.g. cyclopropyl, cyclohexyl),—SO₂C₃₋₈ cycloalkyl (e.g. —SO₂cyclohexyl), —SOC₃₋₆ cycloalkyl (e.g.—SOcyclopropyl), —O-aryl (e.g. —O-phenyl) C₃₋₆alkenyloxy- (e.g.—O-buten-2-yl), C₃₋₆ alkynyloxy- (e.g. —O-buten-2-yl), —C(O)C₁₋₆alkyl(e.g. —C(O)ethyl), —C(O)OC₁₋₆ alkyl (e.g. —C(O)O-methyl),C₁₋₆alkoxy-C₁₋₆alkyl- (e.g. methoxy-ethyl-), nitro, halogen (e.g.fluoro, chloro, bromo), cyano, hydroxyl, —C(O)OH, —NH₂, —NHC₁₋₄ alkyl(e.g. —NHmethyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl) (e.g. —N(methyl)₂),—C(O)N(C₁₋₄ alkyl)(C₁₋₄ alkyl) (e.g. —C(O)N(methyl)₂), —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl) (e.g. —C(O)NHmethyl), —C(O)NH(C₃₋₁₀cycloalkyl) (e.g.—C(O)NHcyclopropyl). More typically, substituents will be selected fromC₁₋₆alkyl (e.g. methyl), C₁₋₆ haloalkyl (e.g. C₁₋₆ fluoroalkyl, e.g.CF₃), C₁₋₆ alkoxy (e.g. OMe), halogen and hydroxy.

When E represents aryl, said aryl suitably represents optionallysubstituted phenyl. Exemplary substituted phenyl groups for E include2-bromophenyl, 2-bromo-4-fluorophenyl-, 2-bromo-5-fluorophenyl-,2-fluoro-5-bromophenyl, 2-chlorophenyl-, 2-fluorophenyl-,3-chlorophenyl-, 3-bromophenyl-, 3-fluorophenyl-, 4-chlorophenyl-,4-fluorophenyl-, 4-bromophenyl-, 4-bromo-2-fluorophenyl,2-chloro-3,6-difluorophenyl), 2,3-dichlorophenyl-, 2,3-difluorophenyl-,2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,4-dichlorophenyl-,2,4-difluororophenyl-, 2,4,6-trifluorophenyl-, 2,5-dichlorophenyl-,2,6-dichlorophenyl-, 2,6-difluorophenyl-, 3,4-dichlorophenyl-,3,4-difluorophenyl-, 3,5-difluorophenyl-, 2,4,5-trifluorophenyl-,3,4,5-trifluorophenyl-, 2,4-dimethylphenyl-, 3-methylphenyl-,3,4-dimethylphenyl-, 4-methylphenyl-, 4-isopropylphenyl-,4-tert-butylphenyl-, 2,4,6-trimethylphenyl-,2-isopropyl-6-methylphenyl-, 2-(trifluoromethyl)phenyl-,4-(trifluoromethyl)phenyl-, 2,4-bis(trifluoromethyl)phenyl-,3,5-bis(trifluoromethyl)phenyl-, 2-methoxyphenyl-, 2,4-dimethoxyphenyl-,2,6-dimethoxyphenyl-, 3-methoxyphenyl-, 4-methoxyphenyl-,4-ethoxyphenyl-, 4-propoxyphenyl-, 4-butoxyphenyl-, 4-pentoxyphenyl-,4-isopropyloxyphenyl-, 3-(cyclopentyloxy)-4-methoxyphenyl-,3,4,5-trimethoxyphenyl-, 3,4-dimethoxyphenyl-, 3,5-dimethoxyphenyl-,4-tetrafluoroethyloxyphenyl, 4-cyanophenyl-, 4-thiomethylphenyl- and4-dimethylaminophenyl. Alternatively, E may represent unsubstitutedphenyl-. Further exemplary substituted phenyl groups include2,3-difluoro-4-methylphenyl, 2-fluoro-5-(trifluoromethyl)phenyl-,2-hydroxy-3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-,3-fluoro-4-(trifluoromethyl)phenyl-,3-fluoro-5-(trifluoromethyl)phenyl-,2-fluoro-4-(trifluoromethyl)phenyl-, 2-fluoro-3-(methyl)phenyl-,3-fluoro-4-(methoxy)phenyl-, 3-hydroxy-4-methoxyphenyl-,4-chloro-3-(trifluoromethyl)phenyl-, 4-chloro-3-methylphenyl,4-bromo-4-ethylphenyl, 2,3,5,6-tetrafluoro-4-(methyl)phenyl-,2,6-difluoro-4-(methoxy)phenyl- and 2-fluoro-4,5-(dimethoxy)phenyl-.

When E represents optionally substituted heteroaryl, examples includepyridinyl (e.g. pyridin-2-yl and pyridin-4-yl) and pyrimidinyl. Specificsubstituents that may be mentioned are one or more e.g. 1, 2 or 3 groupsselected from halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g.methoxy-). An example substituted ring is 1-oxy-pyridin-4-yl-.

In a more preferred embodiment, when A is a monocyclic heteroaryl, A isselected from

In amost preferred embodiment, when A is a monocyclic heteroaryl, A is

In a further amost preferred embodiment, when A is a monocyclicheteroaryl, A is

In yet a amost preferred embodiment, when A is a monocyclic heteroaryl,A is

When A is a bicyclic heteroaryl, A is preferably selected frombenzimidazole and imidazopyridine, such as imidazo[1,2-a]pyridine.

In a more preferred embodiment, when A is a bicyclic heteroaryl, A isselected from

In amost preferred embodiment, when A is a bicyclic heteroaryl, A is

In a further amost preferred embodiment, when A is a bicyclicheteroaryl, A is

In yet a amost preferred embodiment, when A is a bicyclic heteroaryl, Ais

In a preferred embodiment, B is selected from C₃₋₅-heteroalkyl, phenyl,C₅-C₆-heterocyclyl and C₁₋₅ alkylene, wherein said C₁₋₅ alkylene groupmay independently be substituted by alkyl.

More preferably, B is selected from

wherein X₁ is alkyl, N, O or S, preferably methyl or S; and n is aninteger selected from 1 and 2;

wherein o is 0 or 1; and p is 0 or 1; and

wherein R₁ is hydrogen or alkyl and q is 0, 1 or 2.

In a most preferred embodiment, B is

wherein X₁ and n are as defined above.

In a further most preferred embodiment, B is

wherein o is as defined above.

In yet a most preferred embodiment, B is

wherein R₁ and p are as defined above.

In a preferred embodiment, D is a group selected from

wherein

R is absent or is hydrogen; or R forms together with the nitrogen atom aheterocyclic ring of group B;

R₂ is hydrogen, alkyl or cycloalkyl;

Y₁, Y₂, Y₃ and Y₄ are independently selected from CH, N, S and O.

When D is

R is preferably absent and R₂ is preferably hydrogen or alkyl.

When D is

R is preferably hydrogen.

In a further embodiment, D is

wherein R is hydrogen or alkyl.

In a further preferred embodiment, when D is one of the above groups, Rforms together with the nitrogen, to which it is attached, aheterocyclic ring of group B. More preferably, said heterocyclic ring,which is formed by the NR group, is selected from piperidine,pyrrolidine, tetrahydrofuran, morpholine, piperazine, dioxolane anddioxane. Most preferably, when D is one of the above groups, R formstogether with the nitrogen, to which it is attached, a piperidine ringhaving the structure

When D is

Y₁ to Y₄ are preferably CH or N.

In a more preferred embodiment, all of Y₁ to Y₄ are CH.

Even more preferably, one of Y₁ to Y₄ is N, and the other three are CH.

In a further more preferred embodiment, two of Y₁ to Y₄ are N and theother two are CH.

Yet more preferably, three of Y₁, to Y₄ are N and the other one is CH.

Still more preferably, all of Y₁ to Y₄ are N.

When Y₄ is CH, Y₄ may be substituted or unsubstituted.

In a preferred embodiment, Y₄ is CH and is unsubstituted.

In another preferred embodiment, Y₄ is CH and is substituted.

When Y₄ is CH and is substituted, Y₄ is preferably substituted withhalogen or alkyl, most preferably with fluorine or methyl.

E is preferably

wherein

-   -   Y₅ is C;    -   Y₆-Y₁₀ are independently selected from CH, N or O, and    -   R₃, R₄, R₅, R₆, and R₇ are independently selected from hydrogen,        halogen, alkyl, O-alkyl.

In a preferred embodiment, Y₆-Y₁₀ are independently selected from CH andN.

In a preferred embodiment, R₃, R₄, R₅, R₆, and R₇ are independentlyselected from hydrogen, halogen and O-alkyl.

In a further preferred embodiment, R₃, R₄, R₅, R₆, and R₇ areindependently selected from O-phenyl and O-cycloalkyl.

When R₃, R₄, R₅, R₆, and R₇ independently are halogen, R₃, R₄, R₅, R₆,and R₇ are preferably fluorine or chlorine, most preferably fluorine.

When R₃, R₄, R₅, R₆, and R₇ independently are O-alkyl, R₃, R₄, R₅, R₆,and R₇ are O—C₁₋₄alkyl, preferably methoxy, ethoxy, propoxy or butoxy,more preferably methoxy or propoxy.

When R₃, R₄, R₅, R₆, and R₇ independently are O-alkyl, R₃, R₄, R₅, R₆,and R₇ are more most preferably methoxy.

R₃, R₄, R₅, R₆, and R₇ may independently be substituted orunsubstituted. Preferably, up to three of R₃-R₇ are substituted and theother ones are hydrogen.

In a most preferred embodiment, E represents a pyridine ring, whereinone of Y₆-Y₁₀ is N and the other ones are CH.

In another most preferred embodiment, E represents a pyridine ring,wherein two of Y₆-Y₁₀ are N and the other ones are CH.

Said pyrimidine ring may optionally be substituted with halo or alkyl,preferably fluorine and methoxy.

In a specifically preferred embodiment, there is provided a compound offormula (I), which is a compound of formula (IIa) or formula (IIb):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   Z is selected from CH and N;    -   X₁ is selected from alkyl, N, O, S, preferably from CH₂ and S;    -   n is 1 or 2;    -   Y₁ to Y₄ and Y₈ to Y₁₉ are independently selected from CH, N, S        and O, preferably from CH and N,    -   Y₅ is C;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy;        and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a preferred embodiment, Z is CH.

In another preferred embodiment, Z is N.

Most preferably, X₁ is CH₂.

Further most preferably, X₁ is S.

Most preferably, n is 1.

Preferably, one, two, three or all four of Y₁, Y₂, Y₃ and Y₄ are N.

In more preferred embodiments,

-   -   Y₁, Y₂, Y₃ and Y₄ are CH; or    -   Y₁ is N and Y₂, Y₃ and Y₄ are CH; or    -   Y₁ and Y₂ are N and Y₃ and Y₄ are CH; or    -   Y₁ is CH, Y₂ is N and Y₃ and Y₄ are CH; or    -   Y₁ and Y₃ are N and Y₂ and Y₄ are CH; or    -   Y₁ and Y₃ are CH and Y₂ and Y₄ are N; or    -   Y₁ and Y₂ are CH and Y₃ and Y₄ are N; or    -   Y₁, Y₂ and Y₃ are CH and Y₄ is N.

Preferably one or two of Y₈ to Y₁₉ are N and the other of Y₈ to Y₁₉ areCH.

In more preferred embodiments,

-   -   Y₆, Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N and Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇, Y₈, Y₉ are CH and Y₁₀ is N; or    -   Y₆ and Y₇ are N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N, Y₈ is CH, Y₉ is N and Y₁₀ is CH; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ is CH and Y₁₀ is N; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇ and Y₈ are CH, Y₉ is N and Y₁₀ is CH; or

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ and R₆ are both hydrogen; or    -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (IIIa) orformula (IIIb):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   X₁ is selected from alkyl, N, O, S;    -   n is 1 or 2;    -   Y₁ to Y₄ and Y₆ to Y₁₀ are independently selected from CH, N, S        and O, preferably from CH and N,    -   Y₅ is C;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

Most preferably, X, is CH₂.

Further most preferably, X₁ is S.

Most preferably, n is 1.

Preferably, one, two, three or all four of Y₁, Y₂, Y₃ and Y₄ are N.

In more preferred embodiments,

-   -   Y₁, Y₂, Y₃ and Y₄ are CH; or    -   Y₁ is N and Y₂, Y₃ and Y₄ are CH; or    -   Y₁ and Y₂ are N and Y₃ and Y₄ are CH; or    -   Y₁ is CH, Y₂ is N and Y₃ and Y₄ are CH; or    -   Y₁ and Y₃ are N and Y₂ and Y₄ are CH; or    -   Y₁ and Y₃ are CH and Y₂ and Y₄ are N; or    -   Y₁ and Y₂ are CH and Y₃ and Y₄ are N; or    -   Y₁, Y₂ and Y₃ are CH and Y₄ is N.

Preferably one or two of Y₆ to Y₁₉ are N and the other of Y₆ to Y₁₉ areCH.

In more preferred embodiments,

-   -   Y₆, Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N and Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇, Y₈, Y₉ are CH and Y₁₀ is N; or    -   Y₆ and Y₇ are N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N, Y₈ is CH, Y₉ is N and Y₁₀ is CH; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ is CH and Y₁₀ is N; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇ and Y₈ are CH, Y₉ is N and Y₁₀ is CH; or

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ and R₆ are both hydrogen; or    -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (IVa) or formula(IVb):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   Z is selected from CH and N;    -   o is 0 or 1;    -   p is 0 or 1;    -   Y₁ to Y₄ and Y₆ to Y₁₉ are independently selected from CH, N, S        and O, preferably from CH and N,    -   Y₅ is C;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a further embodiment, R₅ is O-phenyl; and

-   -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a preferred embodiment, Z is CH.

In another preferred embodiment, Z is N.

Most preferably, o is 0.

Most preferably, p is 0.

In a further most preferred embodiment, p is 1.

Preferably, one, two, three or all four of Y₁, Y₂, Y₃ and Y₄ are N.

In more preferred embodiments,

-   -   Y₁, Y₂, Y₃ and Y₄ are CH; or    -   Y₁ is N and Y₂, Y₃ and Y₄ are CH; or    -   Y₁ and Y₂ are N and Y₃ and Y₄ are CH; or    -   Y₁ is CH, Y₂ is N and Y₃ and Y₄ are CH; or    -   Y₁ and Y₃ are N and Y₂ and Y₄ are CH; or    -   Y₁ and Y₃ are CH and Y₂ and Y₄ are N; or    -   Y₁ and Y₂ are CH and Y₃ and Y₄ are N; or    -   Y₁, Y₂ and Y₃ are CH and Y₄ is N.

Preferably one or two of Y₆ to Y₁₉ are N and the other of Y₆ to Y₁₉ areCH.

In more preferred embodiments,

-   -   Y₆, Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N and Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇, Y₈, Y₉ are CH and Y₁₀ is N; or    -   Y₆ and Y₇ are N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N, Y₈ is CH, Y₉ is N and Y₁₀ is CH; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ is CH and Y₁₀ is N; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇ and Y₈ are CH, Y₉ is N and Y₁₀ is CH; or

R₅ is preferably hydrogen, fluorine or methoxy.

Further preferably, R₅ is propoxy or O-phenyl.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ and R₆ are both hydrogen; or    -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ is methoxy and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy; or    -   R₅ is propoxy and R₆ is hydrogen; or    -   R₅ is O-phenyl and R₆ is hydrogen; or.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (Va) or formula(Vb):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   o is 0 or 1;    -   p is 0 or 1;    -   Y₁ to Y₄ and Y₆ to Y₁₀ are independently selected from CH, N, S        and O, preferably from CH and N,    -   Y₅ is C;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.    -   In a further embodiment, R₅ is O-phenyl; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a preferred embodiment, Z is CH.

In another preferred embodiment, Z is N.

Most preferably, o is 0.

Most preferably, p is 0.

In a further most preferred embodiment, p is 1.

Preferably, one, two, three or all four of Y₁, Y₂, Y₃ and Y₄ are N.

In more preferred embodiments,

-   -   Y₁, Y₂, Y₃ and Y₄ are CH; or    -   Y₁ is N and Y₂, Y₃ and Y₄ are CH; or    -   Y₁ and Y₂ are N and Y₃ and Y₄ are CH; or    -   Y₁ is CH, Y₂ is N and Y₃ and Y₄ are CH; or    -   Y₁ and Y₃ are N and Y₂ and Y₄ are CH; or    -   Y₁ and Y₃ are CH and Y₂ and Y₄ are N; or    -   Y₁ and Y₂ are CH and Y₃ and Y₄ are N; or    -   Y₁ and Y₂ are CH; Y₃ is N and Y₄ is CH, or    -   Y₁, Y₂ and Y₃ are CH and Y₄ is N.

Preferably one or two of Y₆ to Y₁₀ are N and the other of Y₆ to Y₁₀ areCH.

In more preferred embodiments,

-   -   Y₆, Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N and Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇, Y₈, Y₉ are CH and Y₁₀ is N; or    -   Y₆ and Y₇ are N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N, Y₈ is CH, Y₉ is N and Y₁₀ is CH; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ is CH and Y₁₀ is N; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇ and Y₈ are CH, Y₉ is N and Y₁₀ is CH; or

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ and R₆ are both hydrogen; or    -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (VI):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   Z is selected from CH and N;    -   X₁ is selected from alkyl, N, O, S, preferably from CH₂ or S;    -   n is 1 or 2;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a preferred embodiment, Z is CH.

In another preferred embodiment, Z is N.

Most preferably, X₁ is CH₂.

Further most preferably, X₁ is S.

Most preferably, n is 1.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (VII):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   Z is selected from CH and N;    -   X₁ is selected from alkyl, N, O, S, preferably from CH₂ or S;    -   n is 1 or 2;    -   R₂ is selected from alkyl and cycloalkyl, preferably from methyl        and cyclopropyl;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a preferred embodiment, Z is CH.

In another preferred embodiment, Z is N.

Most preferably, X, is CH₂.

Further most preferably, X₁ is S.

Most preferably, n is 1.

In a preferred embodiment, R₂ is methyl.

In a further preferred embodiment, R₂ is cyclopropyl.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (VIII):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   X₁ is selected from alkyl, N, O, S, preferably from CH₂ or S;    -   n is 1 or 2;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

Most preferably, X, is CH₂.

Further most preferably, X₁ is S.

Most preferably, n is 1.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (IX):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   X₁ is selected from alkyl, N, O, S, preferably from CH₂ or S;    -   n is 1 or 2;    -   R₂ is selected from alkyl and cycloalkyl, preferably from methyl        and cyclopropyl;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

Most preferably, X₁ is CH₂.

Further most preferably, X₁ is S.

Most preferably, n is 1.

In a preferred embodiment, R₂ is methyl.

In a further preferred embodiment, R₂ is cyclopropyl.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (X):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   o is 0 or 1;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

Most preferably, o is 0.

Most preferably, p is 0.

Even most preferably, p is 1.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (XI):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   o is 0 or 1;    -   R₂ is selected from alkyl and cycloalkyl, preferably from methyl        and cyclopropyl;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

Most preferably, o is 0.

Most preferably, p is 0.

Even most preferably, p is 1.

In a preferred embodiment, R₂ is methyl.

In a further preferred embodiment, R₂ is cyclopropyl.

-   -   R₅ is preferably hydrogen, fluorine or methoxy.    -   R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (XIIa) orformula (XIIb):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   Z is selected from CH and N;    -   Y₁ to Y₄ and Y₆ to Y₁₀ are independently selected from CH, N, S        and O, preferably from CH and N,    -   Y₅ is C;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a preferred embodiment, Z is CH.

In another preferred embodiment, Z is N.

Preferably, one, two, three or all four of Y₁, Y₂, Y₃ and Y₄ are N.

In more preferred embodiments,

-   -   Y₁, Y₂, Y₃ and Y₄ are CH; or    -   Y₁ is N and Y₂, Y₃ and Y₄ are CH; or    -   Y₁ and Y₂ are N and Y₃ and Y₄ are CH; or    -   Y₁ is CH, Y₂ is N and Y₃ and Y₄ are CH; or    -   Y₁ and Y₃ are N and Y₂ and Y₄ are CH; or    -   Y₁ and Y₃ are CH and Y₂ and Y₄ are N; or    -   Y₁ and Y₂ are CH and Y₃ and Y₄ are N; or    -   Y₁, Y₂ and Y₃ are CH and Y₄ is N.

Preferably one or two of Y₆ to Y₁₉ are N and the other of Y₆ to Y₁₀ areCH.

In more preferred embodiments,

-   -   Y₆, Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N and Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇, Y₈, Y₉ are CH and Y₁₀ is N; or    -   Y₆ and Y₇ are N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N, Y₈ is CH, Y₉ is N and Y₁₀ is CH; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ is CH and Y₁₀ is N; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇ and Y₈ are CH, Y₉ is N and Y₁₀ is CH; or

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ and R₆ are both hydrogen; or    -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (XIII):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   Z is selected from CH and N;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a preferred embodiment, Z is CH.

In another preferred embodiment, Z is N.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (XIV):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (XVa) or formula(XVb):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   Y₁ to Y₄ and Y₆ to Y₁₀ are independently selected from CH, N, S        and O, preferably from CH and N,    -   Y₅ is C;    -   R₅ is selected from halogen, alkyl, O-alkyl, O-phenyl and        O-cycloalkyl, preferably from halogen, O—C₁₋₄alkyl, O-phenyl and        O-cycloalkyl.    -   In a more preferred embodiment, R₅ is fluorine or chlorine, most        preferably fluorine.    -   In another more preferred embodiment, R₅ is O—C₁₋₄alkyl, such as        methoxy, ethoxy, propoxy or butoxy, most preferably methoxy,        propoxy or propan-2-yloxy.    -   In another more preferred embodiment, R₅ is O-phenyl.    -   In another more preferred embodiment, R₅ is O-cycloalkyl, most        preferably O-cyclohexyl.    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

Preferably, one, two, three or all four of Y₁, Y₂, Y₃ and Y₄ are N.

In more preferred embodiments,

-   -   Y₁, Y₂, Y₃ and Y₄ are CH; or    -   Y₁ is N and Y₂, Y₃ and Y₄ are CH; or    -   Y₁ and Y₂ are N and Y₃ and Y₄ are CH; or    -   Y₁ is CH, Y₂ is N and Y₃ and Y₄ are CH; or    -   Y₁ and Y₃ are N and Y₂ and Y₄ are CH; or    -   Y₁ and Y₃ are CH and Y₂ and Y₄ are N; or    -   Y₁ and Y₂ are CH and Y₃ and Y₄ are N; or    -   Y₁ is N, Y₂ and Y₃ are CH and Y₄ is N; or    -   Y₁, Y₂ and Y₃ are CH and Y₄ is N.

When Y₄ is CH, Y₄ may be substituted or unsubstituted.

In a preferred embodiment, Y₄ is CH and is unsubstituted.

In another preferred embodiment, Y₄ is CH and is substituted.

When Y₄ is CH and is substituted, Y₄ is preferably substituted withhalogen or alkyl, most preferably with fluorine or methyl.

Preferably one or two of Y₆ to Y₁₀ are N and the other of Y₆ to Y₁₀ areCH.

In more preferred embodiments,

-   -   Y₆, Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N and Y₇, Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇, Y₈, Y₉ are CH and Y₁₀ is N; or    -   Y₆ and Y₇ are N and Y₈, Y₉ and Y₁₀ are CH; or    -   Y₆ is CH, Y₇ is N, Y₈ is CH, Y₉ is N and Y₁₀ is CH; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ is CH and Y₁₀ is N; or    -   Y₆ and Y₇ are CH, Y₈ is N, Y₉ and Y₁₀ are CH; or    -   Y₆ is N, Y₇ and Y₈ are CH, Y₉ is N and Y₁₀ is CH; or

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ and R₆ are both hydrogen; or    -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (XVI):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (XVII):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   R₂ is selected from alkyl and cycloalkyl, preferably from methyl        and cyclopropyl;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

In a preferred embodiment, R₂ is methyl.

In a further preferred embodiment, R₂ is cyclopropyl.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In a further specifically preferred embodiment, there is provided acompound of formula (I), which is a compound of formula (XVIII):

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof,wherein

-   -   X₁ is selected from alkyl, N, O, S, preferably from CH₂ or S;    -   n is 1 or 2;    -   R₅ is selected from halogen, alkyl and O-alkyl, preferably from        fluorine and methoxy; and    -   R₆ is selected from hydrogen, alkyl and O-alkyl, preferably from        hydrogen and methoxy.

Most preferably, X₁ is CH₂.

Further most preferably, X₁ is S.

Most preferably, n is 1.

R₅ is preferably hydrogen, fluorine or methoxy.

R₆ is preferably hydrogen or methoxy.

More preferably,

-   -   R₅ is fluorine and R₆ is hydrogen; or    -   R₅ and R₆ are both methoxy.

In one embodiment, the compound of formula (I) is a compound accordingto any one of examples 1 to 1323 or a pharmaceutically acceptable salt,solvate or polymorph thereof, including all tautomers and stereoisomers.

In a preferred embodiment, the compound of formula (I) is a compoundselected from:

-   5-[3-({1,1′-fluoro-[1,1′-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine;-   5-{[2-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine;-   5-{[2-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine;-   4′-fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1′-biphenyl]-2-amine;-   3′,4′-dimethoxy-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1′-biphenyl]-2-amine;-   5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine;-   5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine;-   5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine;-   N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine;-   N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine;-   N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine;-   N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine;-   N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine;-   5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine;-   5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine;-   5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine;-   4′-fluoro-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1′-biphenyl]-2-amine;-   3′,4′-dimethoxy-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1′-biphenyl]-2-amine;-   N-[2-(4-methoxyphenyl)phenyl]-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline;-   2-(4-methoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine;-   2-(4-fluorophenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine;-   4-(4-methyl-4H-1,2,4-triazol-3-yl)-N-[2-(4-phenoxyphenyl)phenyl]aniline;-   3-(3,4-dimethoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine;-   N-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]-4-fluorobenzene-1-sulfonamide;-   N-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]ethyl}-4-fluorobenzene-1-sulfonamide;-   5-(3-{[(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine;-   4-fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]benzene-1-sulfonamide;-   4-fluoro-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl}benzene-1-sulfonamide;-   [(3,4-dimethoxyphenyl)sulfamoyl]({2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl})amine;-   N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide;-   N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide;-   5-(1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-[1-(4-fluorobenzenesulfonyhpiperidin-4-yl]-1,3-thiazol-2-amine;-   5-[1-(4-fluorobenzenesulfonyhpiperidin-4-yl]-1,3,4-thiadiazol-2-amine;-   1-(4-fluorobenzenesulfonyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine;-   N-[(1H-1,3-benzodiazol-5-yl)methyl]-4′-fluoro-[1,1′-biphenyl]-2-amine;-   N-[(1H-1,3-benzodiazol-5-yl)methyl]-3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline;-   N-[(1H-1,3-benzodiazol-5-yl)methyl]-4-fluorobenzene-1-sulfonamide;    and-   [(1H-1,3-benzodiazol-5-yl)methyl][(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amine;    or a pharmaceutically acceptable salt, solvate or polymorph thereof,    including all tautomers and stereoisomers.

In a more preferred embodiment, the compound of formula (I) is acompound selected from:

-   5-(1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   N-[(1H-1,3-benzodiazol-5-yl)methyl]-4′-fluoro-[1,1′-biphenyl]-2-amine;-   N-[(1H-1,3-benzodiazol-5-yl)methyl]-3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline;    and-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline;    or a pharmaceutically acceptable salt, solvate or polymorph thereof,    including all tautomers and stereoisomers.

In an evenly preferred embodiment, the compound of formula (I) is acompound selected from:

-   5-(1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   N-[(1H-1,3-benzodiazol-5-yl)methyl]-4′-fluoro-[1,1′-biphenyl]-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline;    and-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline;    or a pharmaceutically acceptable salt, solvate or polymorph thereof,    including all tautomers and stereoisomers.

In a most preferred embodiment, the compound of formula (I) is acompound selected from:

-   N-[(1H-1,3-benzodiazol-5-yl)methyl]-4′-fluoro-[1,1′-biphenyl]-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline;-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline;    and-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline;    or a pharmaceutically acceptable salt, solvate or polymorph thereof,    including all tautomers and stereoisomers.

In a further most preferred embodiment, the compound of formula (I) is:5-(1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine;or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers.

In a further most preferred embodiment, the compound of formula (I) is:

-   N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline;    or a pharmaceutically acceptable salt, solvate or polymorph thereof,    including all tautomers and stereoisomers.

Synthesis Methods

The compounds of formula (I) of the present invention can be prepared bya method selected from synthesis methods A to R as described in theexample section below. The invention thus further relates to synthesismethods A, B, C, D, E, F, G, H, I, K, L, M, N, O, P, Q and R.

In a preferred embodiment, the compounds of formula (I) of the presentinvention are prepared according to synthesis method A.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method B.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method C.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method D.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method E.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method F.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method G.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method H.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method I.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method K.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method L.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method M.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method N.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method 0.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method P.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method Q.

In a further preferred embodiment, the compounds of formula (I) of thepresent invention are prepared according to synthesis method R.

Therapeutic Uses

Physiological substrates of QC (EC) in mammals are, e.g. amyloidbeta-peptides (3-40), (3-42), (11-40 and (11-42), ABri, ADan, Gastrin,Neurotensin, FPP, CCL 2, CCL 7, CCL 8, CCL 16, CCL 18, Fractalkine,Orexin A, [Gln³]-glucagon(3-29), [GIn⁵]substance P(5-11) and the peptideQYNAD. For further details see table 1. The compounds and/orcombinations according to the present invention and pharmaceuticalcompositions comprising at least one inhibitor of QC (EC) are useful forthe treatment of conditions that can be treated by modulation of QCactivity.

TABLE 1Amino acid sequences of physiological active peptides with an N-terminalglutamine residue, which are prone to be cyclized to final pGlu PeptideAmino acid sequence Function Abeta(1-42)Asp-Ala-Glu-Phe-Arg-His-Asp-Ser- Plays a role inGly-Tyr-Glu-Val-His-His-Gln-Lys- neurodegeneration, e.g. inLeu-Val-Phe-Phe-Ala-Glu-Asp-Val- Alzheimer's Disease, FamilialGly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly- British Dementia, FamilialLeu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Danish Dementia, Down SyndromeAbeta(1-40) Asp-Ala-Glu-Phe-Arg-His-Asp-Ser- Plays a role inGly-Tyr-Glu-Val-His-His-Gln-Lys- neurodegeneration, e.g. inLeu-Val-Phe-Phe-Ala-Glu-Asp-Val- Alzheimer's Disease, FamilialGly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly- British Dementia, FamilialLeu-Met-Val-Gly-Gly-Val-Val Danish Dementia, Down Syndrome Abeta(3-42)Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr- Plays a role inGlu-Val-His-His-Gln-Lys-Leu-Val- neurodegeneration, e.g. inPhe-Phe-Ala-Glu-Asp-Val-Gly-Ser- Alzheimer's Disease, FamilialAsn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met- British Dementia, FamilialVal-Gly-Gly-Val-Val-Ile-Ala Danish Dementia, Down Syndrome Abeta(3-40)Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr- Plays a role inGlu-Val-His-His-Gln-Lys-Leu-Val- neurodegeneration, e.g. inPhe-Phe-Ala-Glu-Asp-Val-Gly-Ser- Alzheimer's Disease, FamilialAsn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met- British Dementia, FamilialVal-Gly-Gly-Val-Val Danish Dementia, Down Syndrome Abeta(11-42)Glu-Val-His-His-Gln-Lys-Leu-Val- Plays a role inPhe-Phe-Ala-Glu-Asp-Val-Gly-Ser- neurodegeneration, e.g. inAsn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met- Alzheimer's Disease, FamilialVal-Gly-Gly-Val-Val-Ile-Ala British Dementia, FamilialDanish Dementia, Down Syndrome Abeta(11-40)Glu-Val-His-His-Gln-Lys-Leu-Val- Plays a role inPhe-Phe-Ala-Glu-Asp-Val-Gly-Ser- neurodegeneration, e.g. inAsn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met- Alzheimer's Disease, FamilialVal-Gly-Gly-Val-Val British Dementia, Familial Danish Dementia, DownSyndrome ABri EASNCFA IRHFENKFAV ETLIC Pyroglutamated form plays aSRTVKKNIIEEN role in Familial British Dementia ADanEASNCFA IRHFENKFAV ETLIC Pyroglutamated form plays a FNLFLNSQEKHYrole in Familial Danish Dementia Gastrin 17 QGPWL EEEEEAYGWM DF (amide)Gastrin stimulates the stomach Swiss-Prot: P01350mucosa to produce and secrete hydrochloric acid and thepancreas to secrete its digestive enzymes. It alsostimulates smooth muscle contraction and increasesblood circulation and water secretion in the stomach and intestine.Neurotensin QLYENKPRRP YIL Neurotensin plays an endocrineSwiss-Prot: P30990 or paracrine role in theregulation of fat metabolism. It causes contraction of smooth muscle.FPP QEP amide A tripeptide related to thyrotrophin releasing hormone(TRH), is found in seminal plasma. Recent evidenceobtained in vitro and in vivo showed that FPP plays animportant role in regulating sperm fertility. TRH QHP amideTRH functions as a regulator of Swiss-Prot: P20396the biosynthesis of TSH in the anterior pituitary gland and as aneurotransmitter/ neuromodulator in the central and peripheral nervoussystems. GnRH QHWSYGL RP(G) amide Stimulates the secretion ofSwiss-Prot: P01148 gonadotropins; it stimulates thesecretion of both luteinizing and follicle-stimulating hormones.CCL16 (small QPKVPEW VNTPSTCCLK Shows chemotactic activity forinducible cytokine YYEKVLPRRL VVGYRKALNC lymphocytes and monocytes A16)HLPAIIFVTK RNREVCTNPN but not neutrophils. Also shows Swiss-Prot: O15467DDWVQEYIKD PNLPLLPTRN potent myelosuppressive LSTVKIITAK NGQPQLLNSQactivity, suppresses proliferation of myeloidprogenitor cells. Recombinant SCYA16 shows chemotacticactivity for monocytes and THP-1 monocytes, but not forresting lymphocytes and neutrophils. Induces a calciumflux in THP-1 cells that were desensitized by priorexpression to RANTES. CCL8 (small QPDSVSI PITCCFNVINChemotactic factor that attracts inducible cytokineRKIPIQRLES YTRITNIQCP monocytes, lymphocytes, A8) KEAVIFKTKR GKEVCADPKEbasophils and eosinophils. May Swiss-Prot: P80075 RWVRDSMKHL DQIFQNLKPplay a role in neoplasia and inflammatory host responses.This protein can bind heparin. CCL2 (MCP-1, small QPDAINA PVTCCYNFTNChemotactic factor that attracts inducible cytokine A2)RKISVQRLAS YRRITSSKCP monocytes and basophils but Swiss-Prot: P13500KEAVIFKTIV AKEICADPKQ not neutrophils or eosinophils.KWVQDSMDHL DKQTQTPKT Augments monocyte anti-tumoractivity. Has been implicated in the pathogenesis of diseasescharacterized by monocytic infiltrates, like psoriasis,rheumatoid arthritis or atherosclerosis. May beinvolved in the recruitment of monocytes into the arterial wallduring the disease process of atherosclerosis. Binds to CCR2 and CCR4.CCL18 (small QVGTNKELC CLVYTSWQIP Chemotactic factor that attractsinducible cytokine QKFIVDYSET SPQCPKPGVI lymphocytes but not monocytesA18) LLTKRGRQIC ADPNKKWVQK or granulocytes. May be Swiss-Prot: P55774YISDLKLNA involved in B cell migration intoB cell follicles in lymph nodes. Attracts naive T lymphocytestoward dendritic cells and activated macrophages inlymph nodes, has chemotactic activity for naive T cells, CD4+and CD8+ T cells and thus may play a role in both humoral andcell-mediated immunity responses. Fractalkine QHHGVT KCNITCSKMTThe soluble form is chemotactic (neurotactin) SKIPVALLIH YQQNQASCGKfor T cells and monocytes, but Swiss-Prot: P78423 RAIILETRQH RLFCADPKEQnot for neutrophils. The WVKDAMQHLD RQAAALTRNG membrane-bound formGTFEKQIGEV KPRTTPAAGG promotes adhesion of those MDESVVLEPE ATGESSSLEPleukocytes to endothelial cells. TPSSQEAQRA LGTSPELPTGMay play a role in regulating VTGSSGTRLP PTPKAQDGGPleukocyte adhesion and VGTELFRVPP VSTAATWQSS migration processes at theAPHQPGPSLW AEAKTSEAPS endothelium binds to CX3CR1. TQDPSTQAST ASSPAPEENAPSEGQRVWGQ GQSPRPENSL EREEMGPVPA HTDAFQDWGP GSMAHVSVVP VSSEGTPSREPVASGSWTPK AEEPIHATMD PQRLGVLITP VPDAQAATRR QAVGLLAFLG LLFCLGVAMFTYQSLQGCPR KMAGEMAEGL RYIPRSCGSN SYVLVPV CCL7 (small inducibleQPVGINT STTCCYRFIN Chemotactic factor that attracts cytokine A7)KKIPKQRLES YRRTTSSHCP monocytes and eosinophils, but Swiss-Prot: P80098REAVIFKTKL DKEICADPTQ not neutrophils. Augments KWVQDFMKHL DKKTQTPKLmonocyte anti-tumor activity. Also induces the release ofgelatinase B. This protein can bind heparin. Binds to CCR1,CCR2 and CCR3. Orexin A (Hypocretin- QPLPDCCRQK TCSCRLYELLNeuropeptide that plays a 1) HGAGNHAAGI LTLsignificant role in the regulation Swiss-Prot O43612of food intake and sleep- wakefulness, possibly bycoordinating the complex behavioral and physiologic responses of thesecomplementary homeostatic functions. It plays also abroader role in the homeostatic regulation of energymetabolism, autonomic function, hormonal balance andthe regulation of body fluids. Orexin-A binds to both OX1Rand OX2R with a high affinity. Substance P RPK PQQFFGLMBelongs to the tachykinins. Tachykinins are active peptideswhich excite neurons, evoke behavioral responses, arepotent vasodilators and secretagogues, and contract(directly or indirectly) many smooth muscles. QYNAD Gln-Tyr-Asn-Ala-AspActs on voltage-gated sodium channels.

Glutamate is found in positions 3, 11 and 22 of the amyloid β-peptide.Among them the mutation from glutamic acid (E) to glutamine (Q) inposition 22 (corresponding to amyloid precursor protein APP 693,Swissprot P05067) has been described as the so called Dutch typecerebroarterial amyloidosis mutation.

The β-amyloid peptides with a pyroglutamic acid residue in position 3,11 and/or 22 have been described to be more cytotoxic and hydrophobicthan the amyloid β-peptides 1-40(42/43) (Saido T. C. 2000 MedicalHypotheses 54(3): 427-429).

The multiple N-terminal variations, e.g. Abeta(3-40), Abeta(3-42),Abeta(11-40) and Abeta (11-42) can be generated by the β-secretaseenzyme β-site amyloid precursor protein-cleaving enzyme (BACE) atdifferent sites (Huse J. T. et al. 2002 J. Biol. Chem. 277 (18):16278-16284), and/or by aminopeptidase or dipeptidylaminopeptidaseprocessing from the full length peptides Abeta(1-40) and Abeta(1-42). Inall cases, cyclization of the then N-terminal occurring glutamic acidresidue is catalyzed by QC.

Transepithelial transducing cells, particularly the gastrin (G) cell,co-ordinate gastric acid secretion with the arrival of food in thestomach. Recent work showed that multiple active products are generatedfrom the gastrin precursor, and that there are multiple control pointsin gastrin biosynthesis. Biosynthetic precursors and intermediates(progastrin and Gly-gastrins) are putative growth factors; theirproducts, the amidated gastrins, regulate epithelial cell proliferation,the differentiation of acid-producing parietal cells andhistamine-secreting enterochromaffin-like (ECL) cells, and theexpression of genes associated with histamine synthesis and storage inECL cells, as well as acutely stimulating acid secretion. Gastrin alsostimulates the production of members of the epidermal growth factor(EGF) family, which in turn inhibit parietal cell function but stimulatethe growth of surface epithelial cells. Plasma gastrin concentrationsare elevated in subjects with Helicobacter pylori, who are known to haveincreased risk of duodenal ulcer disease and gastric cancer (Dockray, G.J. 1999 J Physiol 15 315-324).

The peptide hormone gastrin, released from antral G cells, is known tostimulate the synthesis and release of histamine from ECL cells in theoxyntic mucosa via CCK-2 receptors. The mobilized histamine induces acidsecretion by binding to the H(2) receptors located on parietal cells.Recent studies suggest that gastrin, in both its fully amidated and lessprocessed forms (progastrin and glycine-extended gastrin), is also agrowth factor for the gastrointestinal tract. It has been establishedthat the major trophic effect of amidated gastrin is for the oxynticmucosa of stomach, where it causes increased proliferation of gastricstem cells and ECL cells, resulting in increased parietal and ECL cellmass. On the other hand, the major trophic target of the less processedgastrin (e.g. glycine-extended gastrin) appears to be the colonic mucosa(Koh, T. J. and Chen, D. 2000 Regul Pept 9337-44).

Neurotensin (NT) is a neuropeptide implicated in the pathophysiology ofschizophrenia that specifically modulates neurotransmitter systemspreviously demonstrated to be misregulated in this disorder. Clinicalstudies in which cerebrospinal fluid (CSF) NT concentrations have beenmeasured revealed a subset of schizophrenic patients with decreased CSFNT concentrations that are restored by effective antipsychotic drugtreatment. Considerable evidence also exists concordant with theinvolvement of NT systems in the mechanism of action of antipsychoticdrugs. The behavioral and biochemical effects of centrally administeredNT remarkably resemble those of systemically administered antipsychoticdrugs, and antipsychotic drugs increase NT neurotransmission. Thisconcatenation of findings led to the hypothesis that NT functions as anendogenous antipsychotic. Moreover, typical and atypical antipsychoticdrugs differentially alter NT neurotransmission in nigrostriatal andmesolimbic dopamine terminal regions, and these effects are predictiveof side effect liability and efficacy, respectively (Binder, E. B. etal. 2001 Biol Psychiatry 50 856-872).

Fertilization promoting peptide (FPP), a tripeptide related tothyrotrophin releasing hormone (TRH), is found in seminal plasma. Recentevidence obtained in vitro and in vivo showed that FPP plays animportant role in regulating sperm fertility. Specifically, FPPinitially stimulates nonfertilizing (uncapacitated) spermatozoa to“switch on” and become fertile more quickly, but then arrestscapacitation so that spermatozoa do not undergo spontaneous acrosomeloss and therefore do not lose fertilizing potential. These responsesare mimicked, and indeed augmented, by adenosine, known to regulate theadenylyl cyclase (AC)/cAMP signal transduction pathway. Both FPP andadenosine have been shown to stimulate cAMP production in uncapacitatedcells but inhibit it in capacitated cells, with FPP receptors somehowinteracting with adenosine receptors and G proteins to achieveregulation of AC. These events affect the tyrosine phosphorylation stateof various proteins, some being important in the initial “switching on”,others possibly being involved in the acrosome reaction itself.Calcitonin and angiotensin II, also found in seminal plasma, havesimilar effects in vitro on uncapacitated spermatozoa and can augmentresponses to FPP. These molecules have similar effects in vivo,affecting fertility by stimulating and then maintaining fertilizingpotential. Either reductions in the availability of FPP, adenosine,calcitonin, and angiotensin II or defects in their receptors contributeto male infertility (Fraser, L. R. and Adeoya-Osiguwa, S. A. 2001 VitamHorm 63, 1-28).

CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and fractalkine play an importantrole in pathophysiological conditions, such as suppression ofproliferation of myeloid progenitor cells, neoplasia, inflammatory hostresponses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis,vasculitis, humoral and cell-mediated immunity responses, leukocyteadhesion and migration processes at the endothelium, inflammatory boweldisease, restenosis, pulmonary fibrosis, pulmonary hypertention, liverfibrosis, liver cirrhosis, nephrosclerosis, ventricular remodeling,heart failure, arteriopathy after organ transplantations and failure ofvein grafts.

A number of studies have underlined in particular the crucial role ofMCP-1 for the development of atherosclerosis (Gu, L., et al., (1998)Mol. Cell 2, 275-281; Gosling, J., et al., (1999) J Clin. Invest 103,773-778); rheumatoid arthritis (Gong, J. H., et al., (1997) J Exp. Med186, 131-137; Ogata, H., et al., (1997) J Pathol. 182, 106-114);pancreatitis (Bhatia, M., et al., (2005) Am. J Physiol Gastrointest.Liver Physiol 288, G1259-G1265); Alzheimer's disease (Yamamoto, M., etal., (2005) Am. J Pathol. 166, 1475-1485); lung fibrosis (Inoshima, I.,et al., (2004) Am. J Physiol Lung Cell Mol. Physiol 286, L1038-L1044);renal fibrosis (Wada, T., et al., (2004) J Am. Soc. Nephrol. 15,940-948), and graft rejection (Saiura, A., et al., (2004) Arterioscler.Thromb. Vasc. Biol. 24, 1886-1890). Furthermore, MCP-1 might also play arole in gestosis (Katabuchi, H., et al., (2003) Med Electron Microsc.36, 253-262), as a paracrine factor in tumor development (Ohta, M., etal., (2003) Int. J Oncol. 22, 773-778; Li, S., et al., (2005) J Exp. Med202, 617-624), neuropathic pain (White, F. A., et al., (2005) Proc.Natl. Acad. Sci. U.S.A.) and AIDS (Park, I. W., Wang, J. F., andGroopman, J. E. (2001) Blood 97, 352-358; Coll, B., et al., (2006)Cytokine 34, 51-55).

MCP-1 levels are increased in CSF of AD patients and patients showingmild cognitive impairment (MCI) (Galimberti, D., et al., (2006) Arch.Neurol. 63, 538-543). Furthermore, MCP-1 shows an increased level inserum of patients with MCI and early AD (Clerici, F., et al., (2006)Neurobiol. Aging 27, 1763-1768).

Several cytotoxic T lymphocyte peptide-based vaccines against hepatitisB, human immunodeficiency virus and melanoma were recently studied inclinical trials. One interesting melanoma vaccine candidate alone or incombination with other tumor antigens, is the decapeptide ELA. Thispeptide is a Melan-A/MART-1 antigen immunodominant peptide analog, withan N-terminal glutamic acid. It has been reported that the amino groupand gamma-carboxylic group of glutamic acids, as well as the amino groupand gamma-carboxamide group of glutamines, condense easily to formpyroglutamic derivatives. To overcome this stability problem, severalpeptides of pharmaceutical interest have been developed with apyroglutamic acid instead of N-terminal glutamine or glutamic acid,without loss of pharmacological properties. Unfortunately compared withELA, the pyroglutamic acid derivative (PyrELA) and also the N-terminalacetyl-capped derivative (AcELA) failed to elicit cytotoxic T lymphocyte(CTL) activity. Despite the apparent minor modifications introduced inPyrELA and AcELA, these two derivatives probably have lower affinitythan ELA for the specific class I major histocompatibility complex.Consequently, in order to conserve full activity of ELA, the formationof PyrELA must be avoided (Beck A. et al. 2001, J Pept Res57(6):528-38.).

Orexin A is a neuropeptide that plays a significant role in theregulation of food intake and sleep-wakefulness, possibly bycoordinating the complex behavioral and physiologic responses of thesecomplementary homeostatic functions. It plays also a role in thehomeostatic regulation of energy metabolism, autonomic function,hormonal balance and the regulation of body fluids.

Recently, increased levels of the pentapeptide QYNAD were identified inthe cerebrospinal fluid (CSF) of patients suffering from multiplesclerosis or Guillain-Barré syndrome compared to healthy individuals(Brinkmeier H. et al. 2000, Nature Medicine 6, 808-811). There is a bigcontroversy in the literature about the mechanism of action of thepentapeptide Gln-Tyr-Asn-Ala-Asp (QYNAD), especially its efficacy tointeract with and block sodium channels resulting in the promotion ofaxonal dysfunction, which are involved in inflammatory autoimmunediseases of the central nervous system. But recently, it could bedemonstrated that not QYNAD, but its cyclized, pyroglutamated form,pEYNAD, is the active form, which blocks sodium channels resulting inthe promotion of axonal dysfunction. Sodium channels are expressed athigh density in myelinated axons and play an obligatory role inconducting action potentials along axons within the mammalian brain andspinal cord. Therefore, it is speculated that they are involved inseveral aspects of the pathophysiology of inflammatory autoimmunediseases, especially multiple sclerosis, the Guillain-Barré syndrome andchronic inflammatory demyelinizing polyradiculoneuropathy.

Furthermore, QYNAD is a substrate of the enzyme glutaminyl cyclase (QC,EC 2.3.2.5), which is also present in the brain of mammals, especiallyin human brain. Glutaminyl cyclase catalyzes effectively the formationof pEYNAD from its precursor QYNAD.

Accordingly, the present invention provides the use of the compounds offormula (I) for the preparation of a medicament for the prevention oralleviation or treatment of a disease selected from the group consistingof mild cognitive impairment, Alzheimer's disease, Familial BritishDementia, Familial Danish Dementia, neurodegeneration in Down Syndrome,Huntington's disease, Kennedy's disease, ulcer disease, duodenal cancerwith or w/o Helicobacter pylori infections, colorectal cancer,Zolliger-Ellison syndrome, gastric cancer with or without Helicobacterpylori infections, pathogenic psychotic conditions, schizophrenia,infertility, neoplasia, inflammatory host responses, cancer, malignmetastasis, melanoma, psoriasis, rheumatoid arthritis, atherosclerosis,pancreatitis, restenosis, impaired humoral and cell-mediated immuneresponses, leukocyte adhesion and migration processes in theendothelium, impaired food intake, impaired sleep-wakefulness, impairedhomeostatic regulation of energy metabolism, impaired autonomicfunction, impaired hormonal balance or impaired regulation of bodyfluids, multiple sclerosis, the Guillain-Barré syndrome and chronicinflammatory demyelinizing polyradiculoneuropathy.

Furthermore, by administration of a compound according to the presentinvention to a mammal it can be possible to stimulate the proliferationof myeloid progenitor cells.

In addition, the administration of a QC inhibitor according to thepresent invention can lead to suppression of male fertility.

In a preferred embodiment, the present invention provides the use ofinhibitors of QC (EC) activity in combination with other agents,especially for the treatment of neuronal diseases, artherosclerosis andmultiple sclerosis.

The present invention also provides a method of treatment of theaforementioned diseases comprising the administration of atherapeutically active amount of at least one compound of formula (I) toa mammal, preferably a human.

Most preferably, said method and corresponding uses are for thetreatment of a disease selected from the group consisting of mildcognitive impairment, Alzheimer's disease, Familial British Dementia,Familial Danish Dementia, neurodegeneration in Down Syndrome,Parkinson's disease and Chorea Huntington, comprising the administrationof a therapeutically active amount of at least one compound of formula(I) to a mammal, preferably a human.

Even preferably, the present invention provides a method of treatmentand corresponding uses for the treatment of rheumatoid arthritis,atherosclerosis, pancreatitis and restenosis.

Pharmaceutical Combinations

In a preferred embodiment, the present invention provides a composition,preferably a pharmaceutical composition, comprising at least one QCinhibitor optionally in combination with at least one other agentselected from the group consisting of nootropic agents,neuroprotectants, antiparkinsonian drugs, amyloid protein depositioninhibitors, beta amyloid synthesis inhibitors, antidepressants,anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.

Most preferably, said QC inhibitor is a compound of formula (I) of thepresent invention.

More specifically, the aforementioned other agent is selected from thegroup consisting of beta-amyloid antibodies, vaccines, cysteine proteaseinhibitors, PEP-inhibitors, LiCl, acetylcholinesterase (AChE)inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors ofgamma secretases, inhibitors of aminopeptidases, preferably inhibitorsof dipeptidyl peptidases, most preferably DP IV inhibitors; inhibitorsof neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4),TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptorantagonists, sigma-1 receptor inhibitors, histamine H3 antagonists,immunomodulatory agents, immunosuppressive agents, MCP-1 antagonists oran agent selected from the group consisting of antegren (natalizumab),Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD271, adapalene), BAY 361677 (interleukin-4),matrix-metalloproteinase-inhibitors (e.g. BB 76163), interferon-tau(trophoblastin) and SAIK-MS.

Furthermore, the other agent may be, for example, an anti-anxiety drugor antidepressant selected from the group consisting of

-   -   (a) Benzodiazepines, e.g. alprazolam, chlordiazepoxide,        clobazam, clonazepam, clorazepate, diazepam, fludiazepam,        loflazepate, lorazepam, methaqualone, oxazepam, prazepam,        tranxene,    -   (b) Selective serotonin re-uptake inhibitors (SSRI's), e.g.        citalopram, fluoxetine, fluvoxamine, escitalopram, sertraline,        paroxetine,    -   (c) Tricyclic antidepressants, e.g. amitryptiline, clomipramine,        desipramine, doxepin, imipramine    -   (d) Monoamine oxidase (MAO) inhibitors,    -   (e) Azapirones, e.g. buspirone, tandopsirone,    -   (f) Serotonin-norepinephrine reuptake inhibitors (SNRI's), e.g.        venlafaxine, duloxetine,    -   (g) Mirtazapine,    -   (h) Norepinephrine reuptake inhibitors (NRI's), e.g. reboxetine,    -   (i) Bupropione,    -   (j) Nefazodone,    -   (k) beta-blockers,    -   (I) NPY-receptor ligands: NPY agonists or antagonists.

In a further embodiment, the other agent may be, for example, ananti-multiple sclerosis drug selected from the group consisting of

-   -   a) dihydroorotate dehydrogenase inhibitors, e.g. SC-12267,        teriflunomide, MNA-715, HMR-1279 (syn. to HMR-1715, MNA-279),    -   b) autoimmune suppressant, e.g. laquinimod,    -   c) paclitaxel,    -   d) antibodies, e.g. AGT-1, anti-granulocyte-macrophage        colony-stimulating factor (GM-CSF) monoclonal antibody, Nogo        receptor modulators, ABT-874, alemtuzumab (CAMPATH), anti-OX40        antibody, CNTO-1275, DN-1921, natalizumab (syn. to AN-100226,        Antegren, VLA-4 Mab), daclizumab (syn. to Zenepax, Ro-34-7375,        SMART anti-Tac), J-695, priliximab (syn. to Centara, CEN-000029,        cM-T412), MRA, Dantes, anti-IL-12-antibody,    -   e) peptide nucleic acid (PNA) preparations, e.g. reticulose,    -   f) interferon alpha, e.g. Alfaferone, human alpha interferon        (syn. to Omniferon, Alpha Leukoferon),    -   g) interferon beta, e.g. Frone, interferon beta-1a like Avonex,        Betron (Rebif), interferon beta analogs, interferon        beta-transferrin fusion protein, recombinant interferon beta-1b        like Betaseron,    -   h) interferon tau,    -   i) peptides, e.g. AT-008, AnergiX.MS, Immunokine        (alpha-Immunokine-NNSO3), cyclic peptides like ZD-7349,    -   j) therapeutic enzymes, e.g. soluble CD8 (sCD8),    -   k) multiple sclerosis-specific autoantigen-encoding plasmid and        cytokine-encoding plasmid, e.g. BHT-3009;    -   l) inhibitor of TNF-alpha, e.g. BLX-1002, thalidomide, SH-636,    -   m) TNF antagonists, e.g. solimastat, lenercept (syn. to        RO-45-2081, Tenef use), onercept (sTNFR1), CC-1069,    -   n) TNF alpha, e.g. etanercept (syn. to Enbrel, TNR-001)    -   o) CD28 antagonists, e.g. abatacept,    -   p) Lck tyrosine kinase inhibitors,    -   q) cathepsin K inhibitors,    -   r) analogs of the neuron-targeting membrane transporter protein        taurine and the plant-derived calpain inhibitor leupeptin, e.g.        Neurodur,    -   s) chemokine receptor-1 (CCR1) antagonist, e.g. BX-471,    -   t) CCR2 antagonists,    -   u) AMPA receptor antagonists, e.g. ER-167288-01 and ER-099487,        E-2007, talampanel, v) potassium channel blockers, e.g.        fampridine,    -   w) tosyl-proline-phenylalanine small-molecule antagonists of the        VLA-4/VCAM interaction, e.g. TBC-3342,    -   x) cell adhesion molecule inhibitors, e.g. TBC-772,    -   y) antisense oligonucleotides, e.g. EN-101,    -   z) antagonists of free immunoglobulin light chain (IgLC) binding        to mast cell receptors, e.g. F-991,    -   aa) apoptosis inducing antigens, e.g. Apogen MS,    -   bb) alpha-2 adrenoceptor agonist, e.g. tizanidine (syn. to        Zanaflex, Ternelin, Sirdalvo, Sirdalud, Mionidine),    -   cc) copolymer of L-tyrosine, L-lysine, L-glutamic acid and        L-alanine, e.g. glatiramer acetate (syn. to Copaxone, COP-1,        copolymer-1),    -   dd) topoisomerase II modulators, e.g. mitoxantrone        hydrochloride,    -   ee) adenosine deaminase inhibitor, e.g. cladribine (syn. to        Leustatin, Mylinax, RWJ-26251),    -   ff) interleukin-10, e.g. ilodecakin (syn. to Tenovil, Sch-52000,        CSIF),    -   gg) interleukin-12 antagonists, e.g. lisofylline (syn. to        CT-1501R, LSF, lysofylline),    -   hh) Ethanaminum, e.g. SRI-62-834 (syn. to CRC-8605, NSC-614383),    -   ii) immunomodulators, e.g. SAIK-MS, PNU-156804,        alpha-fetoprotein peptide (AFP), IPDS,    -   jj) retinoid receptor agonists, e.g. adapalene (syn. to        Differin, CD-271),    -   kk) TGF-beta, e.g. GDF-1 (growth and differentiation factor 1),    -   ii) TGF-beta-2, e.g. BetaKine,    -   mm) MMP inhibitors, e.g. glycomed,    -   nn) phosphodiesterase 4 (PDE4) inhibitors, e.g. RPR-122818,    -   oo) purine nucleoside phosphorylase inhibitors, e.g.        9-(3-pyridylmethyl)-9-deazaguanine, peldesine (syn. to BCX-34,        TO-200),    -   mm) alpha-4/beta-1 integrin antagonists, e.g. ISIS-104278,    -   qq) antisense alpha4 integrin (CD49d), e.g. ISIS-17044,        ISIS-27104,    -   rr) cytokine-inducing agents, e.g. nucleosides, ICN-17261,    -   ss) cytokine inhibitors,    -   tt) heat shock protein vaccines, e.g. HSPPC-96,    -   uu) neuregulin growth factors, e.g. GGF-2 (syn. to neuregulin,        glial growth factor 2),    -   vv) cathepsin S-inhibitors,    -   ww) bropirimine analogs, e.g. PNU-56169, PNU-63693,    -   xx) Monocyte chemoattractant protein-1 inhibitors, e.g.        benzimidazoles like MCP-1 inhibitors, LKS-1456, PD-064036,        PD-064126, PD-084486, PD-172084, PD-172386.

Further, the present invention provides pharmaceutical compositions e.g.for parenteral, enteral or oral administration, comprising at least oneQC inhibitor, optionally in combination with at least one of the otheraforementioned agents.

These combinations provide a particularly beneficial effect. Suchcombinations are therefore shown to be effective and useful for thetreatment of the aforementioned diseases. Accordingly, the inventionprovides a method for the treatment of these conditions.

The method comprises either co-administration of at least one QCinhibitor and at least one of the other agents or the sequentialadministration thereof.

Co-administration includes administration of a formulation, whichcomprises at least one QC inhibitor and at least one of the other agentsor the essentially simultaneous administration of separate formulationsof each agent.

Beta-amyloid antibodies and compositions containing the same aredescribed, e.g. in WO/2009/065054, WO/2009/056490, WO/2009/053696,WO/2009/033743, WO/2007/113172, WO/2007/022416, WO 2006/137354, WO2006/118959, WO 2006/103116, WO 2006/095041, WO 2006/081171, WO2006/066233, WO 2006/066171, WO 2006/066089, WO 2006/066049, WO2006/055178, WO 2006/046644, WO 2006/039470, WO 2006/036291, WO2006/026408, WO 2006/016644, WO 2006/014638, WO 2006/014478, WO2006/008661, WO 2005/123775, WO 2005/120571, WO 2005/105998, WO2005/081872, WO 2005/080435, WO 2005/028511, WO 2005/025616, WO2005/025516, WO 2005/023858, WO 2005/018424, WO 2005/011599, WO2005/000193, WO 2004/108895, WO 2004/098631, WO 2004/080419, WO2004/071408, WO 2004/069182, WO 2004/067561, WO 2004/044204, WO2004/032868, WO 2004/031400, WO 2004/029630, WO 2004/029629, WO2004/024770, WO 2004/024090, WO 2003/104437, WO 2003/089460, WO2003/086310, WO 2003/077858, WO 2003/074081, WO 2003/070760, WO2003/063760, WO 2003/055514, WO 2003/051374, WO 2003/048204, WO2003/045128, WO 2003/040183, WO 2003/039467, WO 2003/016466, WO2003/015691, WO 2003/014162, WO 2003/012141, WO 2002/088307, WO2002/088306, WO 2002/074240, WO 2002/046237, WO 2002/046222, WO2002/041842, WO 2001/062801, WO 2001/012598, WO 2000/077178, WO2000/072880, WO 2000/063250, WO 1999/060024, WO 1999/027944, WO1998/044955, WO 1996/025435, WO 1994/017197, WO 1990/014840, WO1990/012871, WO 1990/012870, WO 1989/006242.

The beta-amyloid antibodies may be selected from, for example,polyclonal, monoclonal, chimenic or humanized antibodies. Furthermore,said antibodies may be useful to develop active and passive immunetherapies, i.e. vaccines and monoclonal antibodies. Suitable examples ofbeta-amyloid antibodies are ACU-5A5, huC091 (Acumen/Merck); PF-4360365,RI-1014, RI-1219, RI-409, RN-1219 (Rinat Neuroscience Corp (PfizerInc)); the nanobody therapeutics of Ablynx/Boeh ringer Ingelheim;beta-amyloid-specific humanized monoclonal antibodies of IntellectNeurosciences/IBL; m266, m266.2 (Eli Lilly & Co.); AAB-02 (Elan);bapineuzumab (Elan); BAN-2401 (Bioarctic Neuroscience AB); ABP-102(Abiogen Pharma SpA); BA-27, BC-05 (Takeda); R-1450 (Roche); ESBA-212(ESBATech AG); AZD-3102 (AstraZeneca) and beta-amyloid antibodies ofMindset BioPharmaceuticals Inc.

Especially preferred are antibodies, which recognize the N-terminus ofthe Aβ peptide. A suitable antibody, which recognizes the A13-N-Terminusis, for example Acl-24 (AC Immune SA).

Monoclonal antibodies against beta-amyloid peptide are disclosed in WO2007/068412, WO/2008/156621 and WO/2010/012004. Respective chimeric andhumanized antibodies are disclosed in WO 2008/011348 and WO/2008/060364.Vaccine composition for treating an amyloid-associated disease isdisclosed in WO/2002/096937, WO/2005/014041, WO 2007/068411,WO/2007/097251, WO/2009/029272, WO/2009/054537, WO/2009/090650WO/2009/095857, WO/2010/016912, WO/2010/011947, WO/2010/011999,WO/2010/044464.

Suitable vaccines for treating an amyloid-associated disease are, e.g.Affitopes AD-01 and AD-02 (GlaxoSmithKline), ACC-01 and ACC-02(Elan/Wyeth), CAD-106 (Novartis/Cytos Biotechnology),

Suitable cysteine protease inhibitors are inhibitors of cathepsin B.Inhibitors of cathepsin B and compositions containing such inhibitorsare described, e.g. in WO/2008/077109, WO/2007/038772, WO 2006/060473,WO 2006/042103, WO 2006/039807, WO 2006/021413, WO 2006/021409, WO2005/097103, WO 2005/007199, WO2004/084830, WO 2004/078908, WO2004/026851, WO 2002/094881, WO 2002/027418, WO 2002/021509, WO1998/046559, WO 1996/021655.

Examples of suitable PIMT enhancers are 10-aminoaliphatyl-dibenz[b, f]oxepines described in WO 98/15647 and WO 03/057204, respectively.Further useful according to the present invention are modulators of PIMTactivity described in WO 2004/039773.

Inhibitors of beta secretase and compositions containing such inhibitorsare described, e.g. in WO/2010/094242, WO/2010/058333, WO/2010/021680,WO/2009/108550, WO/2009/042694, WO/2008/054698, WO/2007/051333,WO/2007/021793, WO/2007/019080, WO/2007/019078, WO/2007/011810,WO03/059346, WO2006/099352, WO2006/078576, WO2006/060109, WO2006/057983,WO2006/057945, WO2006/055434, WO2006/044497, WO2006/034296,WO2006/034277, WO2006/029850, WO2006/026204, WO2006/014944,WO2006/014762, WO2006/002004, U.S. Pat. No. 7,109,217, WO2005/113484,WO2005/103043, WO2005/103020, WO2005/065195, WO2005/051914,WO2005/044830, WO2005/032471, WO2005/018545, WO2005/004803,WO2005/004802, WO2004/062625, WO2004/043916, WO2004/013098, WO03/099202,WO03/043987, WO03/039454, U.S. Pat. No. 6,562,783, WO02/098849 andWO02/096897.

Suitable examples of beta secretase inhibitors for the purpose of thepresent invention are WY-25105 (Wyeth); Posiphen, (+)-phenserine(TorreyPines/NIH); LSN-2434074, LY-2070275, LY-2070273, LY-2070102 (EliLilly & Co.); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312,PNU-38773, PNU-90530 (Elan/Pfizer); KMI-370, KMI-358, kmi-008 (KyotoUniversity); OM-99-2, OM-003 (Athenagen Inc.); AZ-12304146(AstraZeneca/Astex); GW-840736X (GlaxoSmithKline plc.), DNP-004089 (DeNovo Pharmaceuticals Ltd.) and CT-21166 (CoMentis Inc.).

Inhibitors of gamma secretase and compositions containing suchinhibitors are described, e.g. in WO/2010/090954, WO/2009/011851,WO/2009/008980, WO/2008/147800, WO/2007/084595, WO2005/008250,WO2006/004880, U.S. Pat. Nos. 7,122,675, 7,030,239, 6,992,081,6,982,264, WO2005/097768, WO2005/028440, WO2004/101562, U.S. Pat. Nos.6,756,511, 6,683,091, WO03/066592, WO03/014075, WO03/013527, WO02/36555,WO01/53255, U.S. Pat. Nos. 7,109,217, 7,101,895, 7,049,296, 7,034,182,6,984,626, WO2005/040126, WO2005/030731, WO2005/014553, U.S. Pat. No.6,890,956, EP 1334085, EP 1263774, WO2004/101538, WO2004/00958,WO2004/089911, WO2004/073630, WO2004/069826, WO2004/039370,WO2004/031139, WO2004/031137, U.S. Pat. Nos. 6,713,276, 6,686,449,WO03/091278, U.S. Pat. Nos. 6,649,196, 6,448,229, WO01/77144 andWO01/66564.

Suitable gamma secretase inhibitors for the purpose of the presentinvention are G51-953, WAY-GSI-A, WAY-GSI-B (Wyeth); MK-0752, MRK-560,L-852505, L-685-458, L-852631, L-852646 (Merck & Co. Inc.); LY-450139,LY-411575, AN-37124 (Eli Lilly & Co.); BMS-299897, BMS-433796(Bristol-Myers Squibb Co.); E-2012 (Eisai Co. Ltd.); EHT-0206, EHT-206(ExonHit Therapeutics SA); NGX-555 (TorreyPines Therapeutics Inc.) andSemagacestat (Eli Lilly).

DP IV-inhibitors and compositions containing such inhibitors aredescribed, e.g. in U.S. Pat. Nos. 6,011,155; 6,107,317; 6,110,949;6,124,305; 6,172,081; WO99/61431, WO99/67278, WO99/67279, DE19834591,WO97/40832, WO95/15309, WO98/19998, WO00/07617, WO99/38501, WO99/46272,WO99/38501, WO01/68603, WO01/40180, WO01/81337, WO01/81304, WO01/55105,WO02/02560, WO01/34594, WO02/38541, WO02/083128, WO03/072556,WO03/002593, WO03/000250, WO03/000180, WO03/000181, EP1258476,WO03/002553, WO03/002531, WO03/002530, WO03/004496, WO03/004498,WO03/024942, WO03/024965, WO03/033524, WO03/035057, WO03/035067,WO03/037327, WO03/040174, WO03/045977, WO03/055881, WO03/057144,WO03/057666, WO03/068748, WO03/068757, WO03/082817, WO03/101449,WO03/101958, WO03/104229, WO03/74500, WO2004/007446, WO2004/007468,WO2004/018467, WO2004/018468, WO2004/018469, WO2004/026822,WO2004/032836, WO2004/033455, WO2004/037169, WO2004/041795,WO2004/043940, WO2004/048352, WO2004/050022, WO2004/052850,WO2004/058266, WO2004/064778, WO2004/069162, WO2004/071454,WO2004/076433, WO2004/076434, WO2004/087053, WO2004/089362,WO2004/099185, WO2004/103276, WO2004/103993, WO2004/108730,WO2004/110436, WO2004/111041, WO2004/112701, WO2005/000846,WO2005/000848, WO2005/011581, WO2005/016911, WO2005/023762,WO2005/025554, WO2005/026148, WO2005/030751, WO2005/033106,WO2005/037828, WO2005/040095, WO2005/044195, WO2005/047297,WO2005/051950, WO2005/056003, WO2005/056013, WO2005/058849,WO2005/075426, WO2005/082348, WO2005/085246, WO2005/087235,WO2005/095339, WO2005/095343, WO2005/095381, WO2005/108382,WO2005/113510, WO2005/116014, WO2005/116029, WO2005/118555,WO2005/120494, WO2005/121089, WO2005/121131, WO2005/123685,WO2006/995613; WO2006/009886; WO2006/013104; WO2006/017292;WO2006/019965; WO2006/020017; WO2006/023750; WO2006/039325;WO2006/041976; WO2006/047248; WO2006/058064; WO2006/058628;WO2006/066747; WO2006/066770 and WO2006/068978.

Suitable DP IV-inhibitors for the purpose of the present invention arefor example Sitagliptin, des-fluoro-sitagliptin (Merck & Co. Inc.);vildagliptin, DPP-728, SDZ-272-070 (Novartis); ABT-279, ABT-341 (AbbottLaboratories); denagliptin, TA-6666 (GlaxoSmithKline plc.); SYR-322(Takeda San Diego Inc.); talabostat (Point Therapeutics Inc.);Ro-0730699, R-1499, R-1438 (Roche Holding AG); FE-999011 (FerringPharmaceuticals); TS-021 (Taisho Pharmaceutical Co. Ltd.); GRC-8200(Glenmark Pharmaceuticals Ltd.); ALS-2-0426 (Alantos PharmaceuticalsHolding Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); SSR-162369(Sanofi-Synthelabo); MP-513 (Mitsubishi Pharma Corp.); DP-893,CP-867534-01 (Pfizer Inc.); TSL-225, TMC-2A (Tanabe Seiyaku Co. Ltd.);PHX-1149 (Phenomenix Corp.); saxagliptin (Bristol-Myers Squibb Co.);PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 (ActivXBiosciences Inc.); sulphostin (Zaidan Hojin); KR-62436 (Korea ResearchInstitute of Chemical Technology); P32/98 (Probiodrug AG); BI-A, BI-B(Boehringer Ingelheim Corp.); SK-0403 (Sanwa Kagaku Kenkyusho Co. Ltd.);and NNC-72-2138 (Novo Nordisk A/S).

Other preferred DP IV-inhibitors are

(i) dipeptide-like compounds, disclosed in WO 99/61431, e.g. N-valylprolyl, O-benzoyl hydroxylamine, alanyl pyrrolidine, isoleucylthiazolidine like L-allo-isoleucyl thiazolidine, L-threo-isoleucylpyrrolidine and salts thereof, especially the fumaric salts, andL-allo-isoleucyl pyrrolidine and salts thereof;

(ii) peptide structures, disclosed in WO 03/002593, e.g. tripeptides;

(iii) peptidylketones, disclosed in WO 03/033524;

(vi) substituted aminoketones, disclosed in WO 03/040174;

(v) topically active DP IV-inhibitors, disclosed in WO 01/14318;

(vi) prodrugs of DP IV-inhibitors, disclosed in WO 99/67278 and WO99/67279; and

(v) glutaminyl based DP IV-inhibitors, disclosed in WO 03/072556 and WO2004/099134.

Suitable beta amyloid synthesis inhibitors for the purpose of thepresent invention are for example Bisnorcymserine (Axonyx Inc.);(R)-flurbiprofen (MCP-7869; Flurizan) (Myriad Genetics);nitroflurbiprofen (NicOx); BGC-20-0406 (Sankyo Co. Ltd.) and BGC-20-0466(BTG plc.), RQ-00000009 (RaQualia Pharma Inc).

Suitable amyloid protein deposition inhibitors for the purpose of thepresent invention are for example SP-233 (Samaritan Pharmaceuticals);AZD-103 (Ellipsis Neurotherapeutics Inc.); AAB-001 (Bapineuzumab),AAB-002, ACC-001 (Elan Corp plc.); Colostrinin (ReGen Therapeuticsplc.); Tramiprosate (Neurochem); AdPEDI-(amyloid-beta1-6)11) (VaxinInc.); MPI-127585, MPI-423948 (Mayo Foundation); SP-08 (GeorgetownUniversity); ACU-5A5 (Acumen/Merck); Transthyretin (State University ofNew York); PTI-777, DP-74, DP 68, Exebryl (ProteoTech Inc.); m266 (EliLilly & Co.); EGb-761 (Dr. Willmar Schwabe GmbH); SPI-014 (SatoriPharmaceuticals Inc.); ALS-633, ALS-499 (Advanced Life Sciences Inc.);AGT-160 (ArmaGen Technologies Inc.); TAK-070 (Takeda Pharmaceutical Co.Ltd.); CHF-5022, CHF-5074, CHF-5096 and CHF-5105 (Chiesi FarmaceuticiSpA.), SEN-1176 and SEN-1329 (Senexis Ltd.), AGT-160 (ArmaGenTechnologies), Davunetide (Allon Therapeutics), ELND-005 (ElanCorp/Transition Therapeutics) and nilvadipine (Archer Pharmaceuticals).

Suitable PDE-4 inhibitors for the purpose of the present invention arefor example Doxofylline (Instituto Biologico Chemioterapica ABC SpA.);idudilast eye drops, tipelukast, ibudilast (Kyorin Pharmaceutical Co.Ltd.); theophylline (Elan Corp.); cilomilast (GlaxoSmithKline plc.);Atopik (Barrier Therapeutics Inc.); tofimilast, CI-1044, PD-189659,CP-220629, PDE 4d inhibitor BHN (Pfizer Inc.); arofylline, LAS-37779(Almirall Prodesfarma SA.); roflumilast, hydroxypumafentrine (AltanaAG), tetomilast (Otska Pharmaceutical Co. Ltd.); tipelukast, ibudilast(Kyorin Pharmaceutical), CC-10004 (Celgene Corp.); HT-0712, IPL-4088(Inflazyme Pharmaceuticals Ltd.); MEM-1414, MEM-1917 (MemoryPharmaceuticals Corp.); oglemilast, GRC-4039 (Glenmark PharmaceuticalsLtd.); AWD-12-281, ELB-353, ELB-526 (Elbion AG); EHT-0202 (ExonHitTherapeutics SA.); ND-1251 (Neuroid SA.); 4AZA-PDE4 (4 AZA BioscienceNV.); AVE-8112 (Sanofi-Aventis); CR-3465 (Rottapharm SpA.); GP-0203,NCS-613 (Centre National de la Recherche Scientifique); KF-19514 (KyowaHakko Kogyo Co. Ltd.); ONO-6126 (Ono Pharmaceutical Co. Ltd.); OS-0217(Dainippon Pharmaceutical Co. Ltd.); IBFB-130011, IBFB-150007,IBFB-130020, IBFB-140301 (IBFB Pharma GmbH); IC-485 (ICOS Corp.);RBx-14016 and RBx-11082 (Ranbaxy Laboratories Ltd.). A preferredPDE-4-inhibitor is Rolipram.

MAO inhibitors and compositions containing such inhibitors aredescribed, e.g. in WO2006/091988, WO2005/007614, WO2004/089351,WO01/26656, WO01/12176, WO99/57120, WO99/57119, WO99/13878, WO98/40102,WO98/01157, WO96/20946, WO94/07890 and WO92/21333.

Suitable MAO-inhibitors for the purpose of the present invention are forexample Linezolid (Pharmacia Corp.); RWJ-416457 (RW JohnsonPharmaceutical Research Institute); budipine (Altana AG); GPX-325(BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine;indantadol (Chiesi Farmaceutici SpA.); moclobemide (Roche Holding AG);SL-25.1131 (Sanofi-Synthelabo); CX-1370 (Burroughs Wellcome Co.); CX-157(Krenitsky Pharmaceuticals Inc.); desoxypeganine (HFArzneimittelforschung GmbH & Co. KG); bifemelane (Mitsubishi-TokyoPharmaceuticals Inc.); RS-1636 (Sankyo Co. Ltd.); esuprone (BASF AG);rasagiline (Teva Pharmaceutical Industries Ltd.); ladostigil (HebrewUniversity of Jerusalem); safinamide (Pfizer), NW-1048 (NewronPharmaceuticals SpA.), EVT-302 (Evotec).

Suitable histamine H3 antagonists for the purpose of the presentinvention are, e.g. ABT-239, ABT-834 (Abbott Laboratories); 3874-H1(Aventis Pharma); UCL-2173 (Berlin Free University), UCL-1470(BioProjet, Societe Civile de Recherche); DWP-302 (DaewoongPharmaceutical Co Ltd); GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.);cipralisant, GT-2203 (Gliatech Inc.); Ciproxifan (INSERM),1S,2S-2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (HokkaidoUniversity); JNJ-17216498, JNJ-5207852 (Johnson & Johnson);NNC-0038-0000-1049 (Novo Nordisk A/S); and Sch-79687 (Schering-Plough).

PEP inhibitors and compositions containing such inhibitors aredescribed, e.g. in JP 01042465, JP 03031298, JP 04208299, WO 00/71144,U.S. Pat. No. 5,847,155; JP 09040693, JP 10077300, JP 05331072, JP05015314, WO 95/15310, WO 93/00361, EP 0556482, JP 06234693, JP01068396, EP 0709373, U.S. Pat. Nos. 5,965,556, 5,756,763, 6,121,311, JP63264454, JP 64000069, JP 63162672, EP 0268190, EP 0277588, EP 0275482,U.S. Pat. Nos. 4,977,180, 5,091,406, 4,983,624, 5,112,847, 5,100,904,5,254,550, 5,262,431, 5,340,832, 4,956,380, EP 0303434, JP 03056486, JP01143897, JP 1226880, EP 0280956, U.S. Pat. No. 4,857,537, EP 0461677,EP 0345428, JP 02275858, U.S. Pat. No. 5,506,256, JP 06192298, EP0618193, JP 03255080, EP 0468469, U.S. Pat. No. 5,118,811, JP 05025125,WO 9313065, JP 05201970, WO 9412474, EP 0670309, EP 0451547, JP06339390, U.S. Pat. Nos. 5,073,549, 4,999,349, EP 0268281, U.S. Pat. No.4,743,616, EP 0232849, EP 0224272, JP 62114978, JP 62114957, U.S. Pat.Nos. 4,757,083, 4,810,721, 5,198,458, 4,826,870, EP 0201742, EP 0201741,U.S. Pat. No. 4,873,342, EP 0172458, JP 61037764, EP 0201743, U.S. Pat.No. 4,772,587, EP 0372484, U.S. Pat. No. 5,028,604, WO 91/18877, JP04009367, JP 04235162, U.S. Pat. No. 5,407,950, WO 95/01352, JP01250370, JP 02207070, U.S. Pat. No. 5,221,752, EP 0468339, JP 04211648,WO 99/46272, WO 2006/058720 and PCT/EP2006/061428.

Suitable prolyl endopeptidase inhibitors for the purpose of the presentinvention are, e.g. Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-Benzothiazole(Probiodrug), Z-321 (Zeria Pharmaceutical Co Ltd.); ONO-1603 (OnoPharmaceutical Co Ltd); JTP-4819 (Japan Tobacco Inc.) and S-17092(Servier).

Other suitable compounds that can be used according to the presentinvention in combination with QC-inhibitors are NPY, an NPY mimetic oran NPY agonist or antagonist or a ligand of the NPY receptors.

Preferred according to the present invention are antagonists of the NPYreceptors.

Suitable ligands or antagonists of the NPY receptors are 3a,4,5,9b-tetrahydro-1h-benz[e]indol-2-yl amine-derived compounds asdisclosed in WO 00/68197.

NPY receptor antagonists which may be mentioned include those disclosedin European patent applications EP 0 614 911, EP 0 747 357, EP 0 747 356and EP 0 747 378; international patent applications WO 94/17035, WO97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; WO00/30674, U.S. Pat. Nos. 5,552,411, 5,663,192 and 5,567,714; 6,114,336,Japanese patent application JP 09157253; international patentapplications WO 94/00486, WO 93/12139, WO 95/00161 and WO 99/15498; U.S.Pat. No. 5,328,899; German patent application DE 393 97 97; Europeanpatent applications EP 355 794 and EP 355 793; and Japanese patentapplications JP 06116284 and JP 07267988. Preferred NPY antagonistsinclude those compounds that are specifically disclosed in these patentdocuments. More preferred compounds include amino acid andnon-peptide-based NPY antagonists. Amino acid and non-peptide-based NPYantagonists which may be mentioned include those disclosed in Europeanpatent applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0747 378; international patent applications WO 94/17035, WO 97/19911, WO97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498; U.S.Pat. Nos. 5,552,411, 5,663,192 and 5,567,714; and Japanese patentapplication JP 09157253. Preferred amino acid and non-peptide-based NPYantagonists include those compounds that are specifically disclosed inthese patent documents.

Particularly preferred compounds include amino acid-based NPYantagonists. Amino acid-based compounds, which may be mentioned includethose disclosed in international patent applications WO 94/17035, WO97/19911, WO 97/19913, WO 97/19914 or, preferably, WO 99/15498.Preferred amino acid-based NPY antagonists include those that arespecifically disclosed in these patent documents, for example BIBP3226and, especially, (R)—N2-(diphenylacetyl)-(R)—N-[1-(4-hydroxy-phenyl)ethyl] arginine amide (Example 4 of international patent application WO99/15498).

M1 receptor agonists and compositions containing such inhibitors aredescribed, e.g. in WO2004/087158, WO91/10664.

Suitable M1 receptor antagonists for the purpose of the presentinvention are for example CDD-0102 (Cognitive Pharmaceuticals);Cevimeline (Evoxac) (Snow Brand Milk Products Co. Ltd.); NGX-267(TorreyPines Therapeutics); sabcomeline (GlaxoSmithKline); alvameline (HLundbeck A/S); LY-593093 (Eli Lilly & Co.); VRTX-3 (VertexPharmaceuticals Inc.); WAY-132983 (Wyeth), CI-101 7/(PD-151832) (PfizerInc.) and MCD-386 (Mitridion Inc.).

Acetylcholinesterase inhibitors and compositions containing suchinhibitors are described, e.g. in WO2006/071274, WO2006/070394,WO2006/040688, WO2005/092009, WO2005/079789, WO2005/039580,WO2005/027975, WO2004/084884, WO2004/037234, WO2004/032929, WO03/101458,WO03/091220, WO03/082820, WO03/020289, WO02/32412, WO01/85145,WO01/78728, WO01/66096, WO00/02549, WO01/00215, WO00/15205, WO00/23057,WO00/33840, WO00/30446, WO00/23057, WO00/15205, WO00/09483, WO00/07600,WO00/02549, WO99/47131, WO99/07359, WO98/30243, WO97/38993, WO97/13754,WO94/29255, WO94/20476, WO94/19356, WO93/03034 and WO92/19238.

Suitable acetylcholinesterase inhibitors for the purpose of the presentinvention are for example Donepezil (Eisai Co. Ltd.); rivastigmine(Novartis AG); (−)-phenserine (TorreyPines Therapeutics); ladostigil(Hebrew University of Jerusalem); huperzine A (Mayo Foundation);galantamine (Johnson & Johnson); Memoquin (Universita di Bologna);SP-004 (Samaritan Pharmaceuticals Inc.); BGC-20-1259 (Sankyo Co. Ltd.);physostigmine (Forest Laboratories Inc.); NP-0361 (Neuropharma SA); ZT-1(Debiopharm); tacrine (Warner-Lambert Co.); metrifonate (Bayer Corp.),INM-176 (Whanln), huperzine A (Neuro-Hitech/Xel Pharmaceutical),mimopezil (Debiopharm) and Dimebon (Medivation/Pfizer).

NMDA receptor antagonists and compositions containing such inhibitorsare described, e.g. in WO2006/094674, WO2006/058236, WO2006/058059,WO2006/010965, WO2005/000216, WO2005/102390, WO2005/079779,WO2005/079756, WO2005/072705, WO2005/070429, WO2005/055996,WO2005/035522, WO2005/009421, WO2005/000216, WO2004/092189,WO2004/039371, WO2004/028522, WO2004/009062, WO03/010159, WO02/072542,WO02/34718, WO01/98262, WO01/94321, WO01/92204, WO01/81295, WO01/32640,WO01/10833, WO01/10831, WO00/56711, WO00/29023, WO00/00197, WO99/53922,WO99/48891, WO99/45963, WO99/01416, WO99/07413, WO99/01416, WO98/50075,WO98/50044, WO98/10757, WO98/05337, WO97/32873, WO97/23216, WO97/23215,WO97/23214, WO96/14318, WO96/08485, WO95/31986, WO95/26352, WO95/26350,WO95/26349, WO95/26342, WO95/12594, WO95/02602, WO95/02601, WO94/20109,WO94/13641, WO94/09016 and WO93/25534.

Suitable NMDA receptor antagonists for the purpose of the presentinvention are for example Memantine (Merz & Co. GmbH); topiramate(Johnson & Johnson); AVP-923 (Neurodex) (Center for Neurologic Study);EN-3231 (Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579)(Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals Inc.); dexanabinol(HU-211; Sinnabidol; PA-50211) (Pharmos); EpiCept NP-1 (DalhousieUniversity); indantadol (V-3381; CNP-3381) (Vernalis); perzinfotel(EAA-090, WAY-126090, EAA-129) (Wyeth); RGH-896 (Gedeon Richter Ltd.);traxoprodil (CP-101606), besonprodil (PD-196860, CI-1041) (Pfizer Inc.);CGX-1007 (Cognetix Inc.); delucemine (NPS-1506) (NPS PharmaceuticalsInc.); EVT-101 (Roche Holding AG); acamprosate (Synchroneuron LLC.);CR-3991, CR-2249, CR-3394 (Rottapharm SpA.); AV-101 (4-CI-kynurenine(4-CI-KYN)), 7-chloro-kynurenic acid (7-CI-KYNA) (VistaGen); NPS-1407(NPS Pharmaceuticals Inc.); YT-1006 (Yaupon Therapeutics Inc.); ED-1812(Sosei R&D Ltd.); himantane (hydrochlorideN-2-(adamantly)-hexamethylen-imine) (RAMS); Lancicemine (AR-R-15896)(AstraZeneca); EVT-102, Ro-25-6981 and Ro-63-1908 (Hoffmann-La RocheAG/Evotec), neramexane (Merz).

Furthermore, the present invention relates to combination therapiesuseful for the treatment of atherosclerosis, restenosis or arthritis,administering a QC inhibitor in combination with another therapeuticagent selected from the group consisting of inhibitors of theangiotensin converting enzyme (ACE); angiotensin II receptor blockers;diuretics; calcium channel blockers (CCB); beta-blockers; plateletaggregation inhibitors; cholesterol absorption modulators; HMG-Co-Areductase inhibitors; high density lipoprotein (HDL) increasingcompounds; renin inhibitors; IL-6 inhibitors; antiinflammatorycorticosteroids; antiproliferative agents; nitric oxide donors;inhibitors of extracellular matrix synthesis; growth factor or cytokinesignal transduction inhibitors; MCP-1 antagonists and tyrosine kinaseinhibitors providing beneficial or synergistic therapeutic effects overeach monotherapy component alone.

Angiotensin II receptor blockers are understood to be those activeagents that bind to the AT1-receptor subtype of angiotensin II receptorbut do not result in activation of the receptor. As a consequence of theblockade of the AT1 receptor, these antagonists can, e.g. be employed asantihypertensive agents.

Suitable angiotensin II receptor blockers which may be employed in thecombination of the present invention include AT₁ receptor antagonistshaving differing structural features, preferred are those withnon-peptidic structures. For example, mention may be made of thecompounds that are selected from the group consisting of valsartan (EP443983), losartan (EP 253310), candesartan (EP 459136), eprosartan (EP403159), irbesartan (EP 454511), olmesartan (EP 503785), tasosartan (EP539086), telmisartan (EP 522314), the compound with the designation E-4177 of the formula

the compound with the designation SC-52458 of the following formula

and the compound with the designation the compound ZD-8731 of theformula

or, in each case, a pharmaceutically acceptable salt thereof.

Preferred AT1-receptor antagonists are those agents that have beenapproved and reached the market, most preferred is valsartan, or apharmaceutically acceptable salt thereof.

The interruption of the enzymatic degradation of angiotensin toangiotensin II with ACE inhibitors is a successful variant for theregulation of blood pressure and thus also makes available a therapeuticmethod for the treatment of hypertension.

A suitable ACE inhibitor to be employed in the combination of thepresent invention is, e.g. a compound selected from the group consistingalacepril, benazepril, benazeprilat; captopril, ceronapril, cilazapril,delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril,moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril andtrandolapril, or in each case, a pharmaceutically acceptable saltthereof.

Preferred ACE inhibitors are those agents that have been marketed, mostpreferred are benazepril and enalapril.

A diuretic is, for example, a thiazide derivative selected from thegroup consisting of chlorothiazide, hydrochlorothiazide,methylclothiazide, and chlorothalidon. The most preferred diuretic ishydrochlorothiazide. A diuretic furthermore comprises a potassiumsparing diuretic such as amiloride or triameterine, or apharmaceutically acceptable salt thereof.

The class of CCBs essentially comprises dihydropyridines (DHPs) andnon-DHPs, such as diltiazem-type and verapamil-type CCBs.

A CCB useful in said combination is preferably a DHP representativeselected from the group consisting of amlodipine, felodipine, ryosidine,isradipine, lacidipine, nicardipine, nifedipine, niguldipine,niludipine, nimodipine, nisoldipine, nitrendipine and nivaldipine, andis preferably a non-DHP representative selected from the groupconsisting of flunarizine, prenylamine, diltiazem, fendiline,gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in eachcase, a pharmaceutically acceptable salt thereof. All these CCBs aretherapeutically used, e.g. as anti-hypertensive, anti-angina pectoris oranti-arrhythmic drugs.

Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine,nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil or, e.g.dependent on the specific CCB, a pharmaceutically acceptable saltthereof. Especially preferred as DHP is amlodipine or a pharmaceuticallyacceptable salt thereof, especially the besylate. An especiallypreferred representative of non-DHPs is verapamil or a pharmaceuticallyacceptable salt, especially the hydrochloride, thereof.

Beta-blockers suitable for use in the present invention includebeta-adrenergic blocking agents (beta-blockers), which compete withepinephrine for beta-adrenergic receptors and interfere with the actionof epinephrine. Preferably, the beta-blockers are selective for thebeta-adrenergic receptor as compared to the alpha-adrenergic receptors,and so do not have a significant alpha-blocking effect. Suitablebeta-blockers include compounds selected from acebutolol, atenolol,betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol,metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol,sotalol and timolol. Where the beta-blocker is an acid or base orotherwise capable of forming pharmaceutically acceptable salts orprodrugs, these forms are considered to be encompassed herein, and it isunderstood that the compounds may be administered in free form or in theform of a pharmaceutically acceptable salt or a prodrug, such as aphysiologically hydrolyzable and acceptable ester. For example,metoprolol is suitably administered as its tartrate salt, propranolol issuitably administered as the hydrochloride salt, and so forth.

Platelet aggregation inhibitors include PLAVIX® (clopidogrel bisulfate),PLETAL® (cilostazol) and aspirin.

Cholesterol absorption modulators include ZETIA® (ezetimibe) and KT6-971(Kotobuki Pharmaceutical Co. Japan).

HMG-Co-A reductase inhibitors (also calledbeta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors orstatins) are understood to be those active agents which may be used tolower lipid levels including cholesterol in blood.

The class of HMG-Co-A reductase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds, which are selected from the group consisting of atorvastatin,cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin,rosuvastatin and simvastatin, or in each case, a pharmaceuticallyacceptable salt thereof.

Preferred HMG-Co-A reductase inhibitors are those agents, which havebeen marketed, most preferred is atorvastatin, pitavastatin orsimvastatin, or a pharmaceutically acceptable salt thereof.

HDL-increasing compounds include, but are not limited to, cholesterolester transfer protein (CETP) inhibitors. Examples of CETP inhibitorsinclude JTT7O5 disclosed in Example 26 of U.S. Pat. No. 6,426,365 issuedJul. 30, 2002, and pharmaceutically acceptable salts thereof.

Inhibition of interleukin 6 mediated inflammation may be achievedindirectly through regulation of endogenous cholesterol synthesis andisoprenoid depletion or by direct inhibition of the signal transductionpathway utilizing interleukin-6 inhibitor/antibody, interleukin-6receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide(ASON), gp130 protein inhibitor/antibody, tyrosine kinaseinhibitors/antibodies, serine/threonine kinase inhibitors/antibodies,mitogen-activated protein (MAP) kinase inhibitors/antibodies,phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclearfactor kappaB (NF-κB) inhibitors/antibodies, IκB kinase (IKK)inhibitors/antibodies, activator protein-1 (AP-1) inhibitors/antibodies,STAT transcription factors inhibitors/antibodies, altered IL-6, partialpeptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokinesignaling) protein, PPAR gamma and/or PPAR beta/delta activators/ligandsor a functional fragment thereof.

A suitable antiinflammatory corticosteroid is dexamethasone.

Suitable antiproliferative agents are cladribine, rapamycin, vincristineand taxol.

A suitable inhibitor of extracellular matrix synthesis is halofuginone.

A suitable growth factor or cytokine signal transduction inhibitor is,e.g. the ras inhibitor R115777.

A suitable tyrosine kinase inhibitor is tyrphostin.

Suitable renin inhibitors are described, e.g. in WO 2006/116435. Apreferred renin inhibitor is aliskiren, preferably in the form of thehemi-fumarate salt thereof.

MCP-1 antagonists may, e.g. be selected from anti-MCP-1 antibodies,preferably monoclonal or humanized monoclonal antibodies, MCP-1expression inhibitors, CCR2-antagonists, TNF-alpha inhibitors, VCAM-1gene expression inhibitors and anti-05a monoclonal antibodies.

MCP-1 antagonists and compositions containing such inhibitors aredescribed, e.g. in WO02/070509, WO02/081463, WO02/060900, US2006/670364,US2006/677365, WO2006/097624, US2006/316449, WO2004/056727, WO03/053368,WO00/198289, WO00/157226, WO00/046195, WO00/046196, WO00/046199,WO00/046198, WO00/046197, WO99/046991, WO99/007351, WO98/006703,WO97/012615, WO2005/105133, WO03/037376, WO2006/125202, WO2006/085961,WO2004/024921, WO2006/074265.

Suitable MCP-1 antagonists are, for instance, C-243 (Telik Inc.);NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis Pharmaceuticals Inc.);ABN-912, NIBR-177 (Novartis AG); CC-11006 (Celgene Corp.); SSR-150106(Sanofi-Aventis); MLN-1202 (Millenium Pharmaceuticals Inc.); AGI-1067,AGIX-4207, AGI-1096 (AtherioGenics Inc.); PRS-211095, PRS-211092(Pharmos Corp.); anti-05a monoclonal antibodies, e.g. neutrazumab (G2Therapies Ltd.); AZD-6942 (AstraZeneca plc.); 2-mercaptoimidazoles(Johnson & Johnson); TEI-E00526, TEI-6122 (Deltagen); RS-504393 (RocheHolding AG); SB-282241, SB-380732, ADR-7 (GlaxoSmithKline); anti-MCP-1monoclonal antibodies (Johnson & Johnson).

Combinations of QC-inhibitors with MCP-1 antagonists may be useful forthe treatment of inflammatory diseases in general, includingneurodegenerative diseases.

Combinations of QC-inhibitors with MCP-1 antagonists are preferred forthe treatment of Alzheimer's disease.

Most preferably the QC inhibitor is combined with one or more compoundsselected from the following group:

PF-4360365, m266, bapineuzumab, R-1450, Posiphen, (+)-phenserine,MK-0752, LY-450139, E-2012, (R)-flurbiprofen, AZD-103, AAB-001(Bapineuzumab), Tramiprosate, EGb-761, TAK-070, Doxofylline,theophylline, cilomilast, tofimilast, roflumilast, tetomilast,tipelukast, ibudilast, HT-0712, MEM-1414, oglemilast, Linezolid,budipine, isocarboxazid, phenelzine, tranylcypromine, indantadol,moclobemide, rasagiline, ladostigil, safinamide, ABT-239, ABT-834,GSK-189254A, Ciproxifan, JNJ-17216498, Fmoc-Ala-Pyrr-CN,Z-Phe-Pro-Benzothiazole, Z-321, ONO-1603, JTP-4819, S-17092, BIBP3226;(R)—N2-(diphenylacetyl)-(R)—N-[1-(4-hydroxyphenyl) ethyl] arginineamide, Cevimeline, sabcomeline, (PD-151832), Donepezil, rivastigmine,(−)-phenserine, ladostigil, galantamine, tacrine, metrifonate,Memantine, topiramate, AVP-923, EN-3231, neramexane, valsartan,benazepril, enalapril, hydrochlorothiazide, amlodipine, diltiazem,isradipine, nicardipine, nifedipine, nimodipine, nisoldipine,nitrendipine, verapamil, amlodipine, acebutolol, atenolol, betaxolol,bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol,nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol,timolol, PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol), aspirin,ZETIA® (ezetimibe) and KT6-971, statins, atorvastatin, pitavastatin orsimvastatin; dexamethasone, cladribine, rapamycin, vincristine, taxol,aliskiren, C-243, ABN-912, SSR-150106, MLN-1202 and betaferon.

In particular, the following combinations are considered:

-   -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with Atorvastatin for the treatment and/or        prevention of artherosclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with immunosuppressive agents, preferably        rapamycin for the prevention and/or treatment of restenosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with immunosuppressive agents, preferably        paclitaxel for the prevention and/or treatment of restenosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with AChE inhibitors, preferably Donepezil,        for the prevention and/or treatment of Alzheimer's disease,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with interferones, preferably Aronex, for        the prevention and/or treatment of multiple sclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with interferones, preferably betaferon,        for the prevention and/or treatment of multiple sclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with interferones, preferably Rebif, for        the prevention and/or treatment of multiple sclerosis    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with Copaxone, for the prevention and/or        treatment of multiple sclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with dexamethasone, for the prevention        and/or treatment of restenosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with dexamethasone, for the prevention        and/or treatment of atherosclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with dexamethasone, for the prevention        and/or treatment of rheumatoid arthritis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with HMG-Co-A-reductase inhibitors, for the        prevention and/or treatment of restenosis, wherein the        HMG-Co-A-reductase inhibitor is selected from atorvastatin,        cerivastatin, fluvastatin, lovastatin, pitavastatin,        pravastatin, rosuvastatin and simvastatin,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with HMG-Co-A reductase inhibitors, for the        prevention and/or treatment of atherosclerosis wherein the        HMG-Co-A-reductase inhibitor is selected from atorvastatin,        cerivastatin, fluvastatin, lovastatin, pitavastatin,        pravastatin, rosuvastatin and simvastatin,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with HMG-Co-A reductase inhibitors, for the        prevention and/or treatment of rheumatoid arthritis wherein the        HMG-Co-A-reductase inhibitor is selected from atorvastatin,        cerivastatin, fluvastatin, lovastatin, pitavastatin,        pravastatin, rosuvastatin and simvastatin,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with amyloid-beta antibodies for the        prevention and/or treatment of mild cognitive impairment,        wherein the amyloid-beta antibody is Acl-24,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with amyloid-beta antibodies for the        prevention and/or treatment of Alzheimer's disease, wherein the        amyloid-beta antibody is Acl-24,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with amyloid-beta antibodies for the        prevention and/or treatment of neurodegeneration in Down        Syndrome, wherein the amyloid-beta antibody is Acl-24,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with beta-secretase inhibitors for the        prevention and/or treatment of mild cognitive impairment,        wherein the beta-secretase inhibitor is selected from WY-25105,        GW-840736X and CTS-21166,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with beta-secretase inhibitors for the        prevention and/or treatment of Alzheimer's disease, wherein the        beta-secretase inhibitor is selected from WY-25105, GW-840736X        and CTS-21166,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with beta-secretase inhibitors for the        prevention and/or treatment of neurodegeneration in Down        Syndrome, wherein the beta-secretase inhibitor is selected from        WY-25105, GW-840736X and CTS-21166,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with gamma-secretase inhibitors for the        prevention and/or treatment of mild cognitive impairment,        wherein the gamma-secretase inhibitor is selected from        LY-450139, LY-411575 and AN-37124,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with gamma-secretase inhibitors for the        prevention and/or treatment of Alzheimer's disease, wherein the        gamma-secretase inhibitor is selected from LY-450139, LY-411575        and AN-37124,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples 1 to        1323, in combination with gamma-secretase inhibitors for the        prevention and/or treatment of neurodegeneration in Down        Syndrome, wherein the gamma-secretase inhibitor is selected from        LY-450139, LY-411575 and AN-37124.

Such a combination therapy is in particular useful for AD, FAD, FDD andneurodegeneration in Down syndrome as well as atherosclerosis,rheumatoid arthritis, restenosis and pancreatitis.

Such combination therapies might result in a better therapeutic effect(less proliferation as well as less inflammation, a stimulus forproliferation) than would occur with either agent alone.

With regard to the specific combination of inhibitors of QC and furthercompounds it is referred in particular to WO 2004/098625 in this regard,which is incorporated herein by reference.

Pharmaceutical Compositions

To prepare the pharmaceutical compositions of this invention, at leastone compound of formula (I) optionally in combination with at least oneof the other aforementioned agents can be used as the activeingredient(s). The active ingredient(s) is intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration, e.g.,oral or parenteral such as intramuscular. In preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed. Thus, for liquid oral preparations, such as for example,suspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like; for solid oral preparations such as, forexample, powders, capsules, gelcaps and tablets, suitable carriers andadditives include starches, sugars, diluents, granulating agents,lubricants, binders, disintegrating agents and the like. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. If desired, tablets may be sugar coatedor enteric coated by standard techniques. For parenterals, the carrierwill usually comprise sterile water, though other ingredients, forexample, for purposes such as aiding solubility or for preservation, maybe included.

Injectable suspensions may also prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient(s) necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per dosage unit, e.g., tablet, capsule, powder, injection, suppository,teaspoonful and the like, from about 0.03 mg to 100 mg/kg (preferred0.1-30 mg/kg) and may be given at a dosage of from about 0.1-300 mg/kgper day (preferred 1-50 mg/kg per day) of each active ingredient orcombination thereof. The dosages, however, may be varied depending uponthe requirement of the patients, the severity of the condition beingtreated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofeach active ingredient or combinations thereof of the present invention.

The tablets or pills of the compositions of the present invention can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

This liquid forms in which the compositions of the present invention maybe incorporated for administration orally or by injection include,aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

The pharmaceutical composition may contain between about 0.01 mg and 100mg, preferably about 5 to 50 mg, of each compound, and may beconstituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixirs,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbetalactose, corn sweeteners, natural and synthetic gums such as acacia,tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.

The liquid forms in suitable flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compounds or combinations of the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

Compounds or combinations of the present invention may also be deliveredby the use of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamid-ephenol, or polyethyl eneoxidepolyllysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, polyacticacid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds or combinations of this invention may be administered in anyof the foregoing compositions and according to dosage regimensestablished in the art whenever treatment of the addressed disorders isrequired.

The daily dosage of the products may be varied over a wide range from0.01 to 1.000 mg per mammal per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of each active ingredient or combinationsthereof for the symptomatic adjustment of the dosage to the patient tobe treated. An effective amount of the drug is ordinarily supplied at adosage level of from about 0.1 mg/kg to about 300 mg/kg of body weightper day. Preferably, the range is from about 1 to about 50 mg/kg of bodyweight per day. The compounds or combinations may be administered on aregimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of disease condition. In addition,factors associated with the particular patient being treated, includingpatient age, weight, diet and time of administration, will result in theneed to adjust dosages.

In a further aspect, the invention also provides a process for preparinga pharmaceutical composition comprising at least one compound of formula(I), optionally in combination with at least one of the otheraforementioned agents and a pharmaceutically acceptable carrier.

The compositions are preferably in a unit dosage form in an amountappropriate for the relevant daily dosage.

Suitable dosages, including especially unit dosages, of the compounds ofthe present invention include the known dosages including unit doses forthese compounds as described or referred to in reference text such asthe British and US Pharmacopoeias, Remington's Pharmaceutical Sciences(Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, ThePharmaceutical Press) (for example see the 31st Edition page 341 andpages cited therein) or the above mentioned publications.

EXAMPLES

In a further embodiment, the present invention provides compounds offormula (IIa) and (IIb), wherein X₁, n, Z, Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇,Y₈, Y₉, Y₁₀, R₅, and R₆ are as defined in examples 1 to 265:

Comp X₁ n Z Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆  1 CH₂ 1 CH CH CH CH CHC CH CH CH CH CH H H  2 CH₂ 1 N CH CH CH CH C CH CH CH CH CH H H  3 S 1N CH CH CH CH C CH CH CH CH CH H H  4 CH₂ 1 CH CH CH CH CH C N CH CH CHCH H H  5 CH₂ 1 N CH CH CH CH C N CH CH CH CH H H  6 S 1 N CH CH CH CH CN CH CH CH CH H H  7 CH₂ 1 CH CH CH CH CH C CH N CH CH CH H H  8 CH₂ 1 NCH CH CH CH C CH N CH CH CH H H  9 S 1 N CH CH CH CH C CH N CH CH CH H H 10 CH₂ 1 CH CH CH CH CH C N CH CH CH N H H  11 CH₂ 1 N CH CH CH CH C NCH CH CH N H H  12 S 1 N CH CH CH CH C N CH CH CH N H H  13 CH₂ 1 CH CHCH CH CH C N N CH CH CH H H  14 CH₂ 1 N CH CH CH CH C N N CH CH CH H H 15 S 1 N CH CH CH CH C N N CH CH CH H H  16 CH₂ 1 CH CH CH CH CH C CH NCH N CH H absent  17 CH₂ 1 N CH CH CH CH C CH N CH N CH H  18 S 1 N CHCH CH CH C CH N CH N CH H  19 CH2 1 CH CH CH CH CH C CH CH N CH N absentH  20 CH2 1 N CH CH CH CH C CH CH N CH N H  21 S 1 N CH CH CH CH C CH CHN CH N H  22 1 C CH CH CH CH H H  23 CH₂ 1 CH CH CH CH CH C CH CH N CHCH absent H  24 CH₂ 1 N CH CH CH CH C CH CH N CH CH H  25 S 1 N CH CH CHCH C CH CH N CH CH H  26 CH₂ 1 CH N CH CH CH C CH CH CH CH CH H H  27CH₂ 1 N N CH CH CH C CH CH CH CH CH H H  28 S 1 N N CH CH CH C CH CH CHCH CH H H  29 CH₂ 1 CH N CH CH CH C N CH CH CH CH H H  30 CH₂ 1 N N CHCH CH C N CH CH CH CH H H  31 S 1 N N CH CH CH C N CH CH CH CH H H  32CH₂ 1 CH N CH CH CH C CH N CH CH CH H H  33 CH₂ 1 N N CH CH CH C CH N CHCH CH H H  34 S 1 N N CH CH CH C CH N CH CH CH H H  35 CH₂ 1 CH N CH CHCH C N CH CH CH N H H  36 CH₂ 1 N N CH CH CH C N CH CH CH N H H  37 S 1N N CH CH CH C N CH CH CH N H H  38 CH₂ 1 CH N CH CH CH C CH CH N CH Nabsent H  39 CH₂ 1 N N CH CH CH C CH CH N CH N H  40 S 1 N N CH CH CH CCH CH N CH N H  41 CH₂ 1 CH N CH CH CH C N CH CH CH CH H H  42 CH₂ 1 N NCH CH CH C N CH CH CH CH H H  43 S 1 N N CH CH CH C N CH CH CH CH H H 44 CH₂ 1 CH N N CH CH C CH CH N CH N absent H  45 CH₂ 1 N N N CH CH CCH CH N CH N H  46 S 1 N N N CH CH C CH CH N CH N H  47 CH₂ 1 CH N N CHCH C CH CH CH CH CH H H  48 CH₂ 1 N N N CH CH C CH CH CH CH CH H H  49 S1 N N N CH CH C CH CH CH CH CH H H  50 CH₂ 1 CH CH N CH CH C CH CH CH CHCH H H  51 CH₂ 1 N CH N CH CH C CH CH CH CH CH H H  52 S 1 N CH N CH CHC CH CH CH CH CH H H  53 CH₂ 1 CH CH N CH CH C N CH CH CH CH H H  54 CH₂1 N CH N CH CH C N CH CH CH CH H H  55 S 1 N CH N CH CH C N CH CH CH CHH H  56 CH₂ 1 CH CH N CH CH C CH N CH CH CH H H  57 CH₂ 1 N CH N CH CH CCH N CH CH CH H H  58 S 1 N CH N CH CH C CH N CH CH CH H H  59 CH₂ 1 CHCH N CH CH C CH N CH N CH H absent  60 CH₂ 1 N CH N CH CH C CH N CH N CHH  61 S 1 N CH N CH CH C CH N CH N CH H  62 CH₂ 1 CH CH N CH CH C N CHCH N CH H H  63 CH₂ 1 N CH N CH CH C N CH CH N CH H H  64 S 1 N CH N CHCH C N CH CH N CH H H  65 CH₂ 1 CH CH N CH CH C CH CH N CH N absent H 66 CH₂ 1 N CH N CH CH C CH CH N CH N H  67 S 1 N CH N CH CH C CH CH NCH N H  68 CH₂ 1 CH CH N CH CH C CH CH N CH CH absent H  69 CH₂ 1 N CH NCH CH C CH CH N CH CH H  70 S 1 N CH N CH CH C CH CH N CH CH H  71 CH₂ 1CH N CH N CH C CH CH CH CH CH H H  72 CH₂ 1 N N CH N CH C CH CH CH CH CHH H  73 S 1 N N CH N CH C CH CH CH CH CH H H  74 CH₂ 1 CH N CH N CH C NCH CH CH CH H H  75 CH₂ 1 N N CH N CH C N CH CH CH CH H H  76 S 1 N N CHN CH C N CH CH CH CH H H  77 CH₂ 1 CH N CH N CH C CH N CH CH CH H H  78CH₂ 1 N N CH N CH C CH N CH CH CH H H  79 S 1 N N CH N CH C CH N CH CHCH H H  80 CH₂ 1 CH CH N CH N C CH CH CH CH CH H H  81 CH₂ 1 N CH N CH NC CH CH CH CH CH H H  82 S 1 N CH N CH N C CH CH CH CH CH H H  83 CH₂ 1CH CH CH N N C CH CH CH CH CH H H  84 CH₂ 1 N CH CH N N C CH CH CH CH CHH H  85 S 1 N CH CH N N C CH CH CH CH CH H H  86 CH₂ 1 CH CH CH CH N CCH CH CH CH CH H H  87 CH₂ 1 N CH CH CH N C CH CH CH CH CH H H  88 S 1 NCH CH CH N C CH CH CH CH CH H H  89 CH₂ 1 CH CH CH CH N C CH CH N CH CHabsent H  90 CH₂ 1 N CH CH CH N C CH CH N CH CH H  91 S 1 N CH CH CH N CCH CH N CH CH H  92 CH₂ 1 CH CH CH CH CH C CH CH CH CH CH F H  93 CH₂ 1N CH CH CH CH C CH CH CH CH CH F H  94 S 1 N CH CH CH CH C CH CH CH CHCH F H  95 CH₂ 1 CH CH CH CH CH C N CH CH CH CH F H  96 CH₂ 1 N CH CH CHCH C N CH CH CH CH F H  97 S 1 N CH CH CH CH C N CH CH CH CH F H  98 CH₂1 CH CH CH CH CH C CH N CH CH CH F H  99 CH₂ 1 N CH CH CH CH C CH N CHCH CH F H 100 S 1 N CH CH CH CH C CH N CH CH CH F H 101 CH₂ 1 CH CH CHCH CH C N CH CH CH N F H 102 CH₂ 1 N CH CH CH CH C N CH CH CH N F H 103S 1 N CH CH CH CH C N CH CH CH N F H 104 CH₂ 1 CH CH CH CH CH C N N CHCH CH F H 105 CH₂ 1 N CH CH CH CH C N N CH CH CH F H 106 S 1 N CH CH CHCH C N N CH CH CH F H 107 CH₂ 1 CH CH CH CH CH C CH N CH N CH F absent108 CH₂ 1 N CH CH CH CH C CH N CH N CH F 109 S 1 N CH CH CH CH C CH N CHN CH F 110 CH₂ 1 CH CH CH CH CH C CH CH N CH N absent 111 CH₂ 1 N CH CHCH CH C CH CH N CH N 112 S 1 N CH CH CH CH C CH CH N CH N 113 CH₂ 1 CHCH CH CH CH C CH CH N CH CH absent H 114 CH₂ 1 N CH CH CH CH C CH CH NCH CH H 115 S 1 N CH CH CH CH C CH CH N CH CH H 116 CH₂ 1 CH N CH CH CHC CH CH CH CH CH F H 117 CH₂ 1 N N CH CH CH C CH CH CH CH CH F H 118 S 1N N CH CH CH C CH CH CH CH CH F H 119 CH₂ 1 CH N CH CH CH C N CH CH CHCH F H 120 CH₂ 1 N N CH CH CH C N CH CH CH CH F H 121 S 1 N N CH CH CH CN CH CH CH CH F H 122 CH₂ 1 CH N CH CH CH C CH N CH CH CH F H 123 CH₂ 1N N CH CH CH C CH N CH CH CH F H 124 S 1 N N CH CH CH C CH N CH CH CH FH 125 CH₂ 1 CH N CH CH CH C N CH CH CH F H 126 CH₂ 1 N N CH CH CH C N CHCH CH F H 127 S 1 N N CH CH CH C N CH CH CH F H 128 CH₂ 1 CH N CH CH CHC CH CH N CH N absent H 129 CH₂ 1 N N CH CH CH C CH CH N CH N H 130 S 1N N CH CH CH C CH CH N CH N H 131 CH₂ 1 CH N N CH CH C CH CH CH CH CH FH 132 CH₂ 1 N N N CH CH C CH CH CH CH CH F H 133 S 1 N N N CH CH C CH CHCH CH CH F H 134 CH₂ 1 CH N N CH CH C CH CH N CH N absent H 135 CH₂ 1 NN N CH CH C CH CH N CH N H 136 S 1 N N N CH CH C CH CH N CH N H 137 CH₂1 CH CH N CH CH C CH CH CH CH CH F H 138 CH₂ 1 N CH N CH CH C CH CH CHCH CH F H 139 S 1 N CH N CH CH C CH CH CH CH CH F H 140 CH₂ 1 CH CH N CHCH C N CH CH CH CH F H 141 CH₂ 1 N CH N CH CH C N CH CH CH CH F H 142 S1 N CH N CH CH C N CH CH CH CH F H 143 CH₂ 1 CH CH N CH CH C CH N CH CHCH F H 144 CH₂ 1 N CH N CH CH C CH N CH CH CH F H 145 S 1 N CH N CH CH CCH N CH CH CH F H 146 CH₂ 1 CH CH N CH CH C CH N CH N CH F absent 147CH₂ 1 N CH N CH CH C CH N CH N CH F 148 S 1 N CH N CH CH C CH N CH N CHF 149 CH₂ 1 CH CH N CH CH C N CH CH N CH F absent 150 CH₂ 1 N CH N CH CHC N CH CH N CH F 151 S 1 N CH N CH CH C N CH CH N CH F 152 CH₂ 1 CH CH NCH CH C CH CH N CH N absent H 153 CH₂ 1 N CH N CH CH C CH CH N CH N H154 S 1 N CH N CH CH C CH CH N CH N H 155 CH₂ 1 CH N CH N CH C CH CH CHCH CH F H 156 CH₂ 1 N N CH N CH C CH CH CH CH CH F H 157 S 1 N N CH N CHC CH CH CH CH CH F H 158 CH₂ 1 CH N CH N CH C N CH CH CH CH F H 159 CH₂1 N N CH N CH C N CH CH CH CH F H 160 S 1 N N CH N CH C N CH CH CH CH FH 161 CH₂ 1 CH N CH N CH C CH N CH CH CH F H 162 CH₂ 1 N N CH N CH C CHN CH CH CH F H 163 S 1 N N CH N CH C CH N CH CH CH F H 164 CH₂ 1 CH CH NCH N C CH CH CH CH CH F H 165 CH₂ 1 N CH N CH N C CH CH CH CH CH F H 166S 1 N CH N CH N C CH CH CH CH CH F H 167 CH₂ 1 CH CH CH N N C CH CH CHCH CH F H 168 CH₂ 1 N CH CH N N C CH CH CH CH CH F H 169 S 1 N CH CH N NC CH CH CH CH CH F H 170 CH₂ 1 CH CH CH CH N C CH CH CH CH CH F H 171CH₂ 1 N CH CH CH N C CH CH CH CH CH F H 172 S 1 N CH CH CH N C CH CH CHCH CH F H 173 CH₂ 1 CH CH CH CH N C CH N CH CH CH F H 174 CH₂ 1 N CH CHCH N C CH N CH CH CH F H 175 S 1 N CH CH CH N C CH N CH CH CH F H 176CH₂ 1 CH CH CH CH CH C CH CH CH CH CH OMe OMe 177 CH₂ 1 N CH CH CH CH CCH CH CH CH CH OMe OMe 178 S 1 N CH CH CH CH C CH CH CH CH CH OMe OMe179 CH₂ 1 CH CH CH CH CH C N CH CH CH CH OMe OMe 180 CH₂ 1 N CH CH CH CHC N CH CH CH CH OMe OMe 181 S 1 N CH CH CH CH C N CH CH CH CH OMe OMe182 CH₂ 1 CH CH CH CH CH C CH N CH CH CH OMe OMe 183 CH₂ 1 N CH CH CH CHC CH N CH CH CH OMe OMe 184 S 1 N CH CH CH CH C CH N CH CH CH OMe OMe185 CH₂ 1 CH CH CH CH CH C N CH CH CH N OMe OMe 186 CH₂ 1 N CH CH CH CHC N CH CH CH N OMe OMe 187 S 1 N CH CH CH CH C N CH CH CH N OMe OMe 188CH₂ 1 CH CH CH CH CH C N N CH CH CH OMe OMe 189 CH₂ 1 N CH CH CH CH C NN CH CH CH OMe OMe 190 S 1 N CH CH CH CH C N N CH CH CH OMe OMe 191 CH₂1 CH CH CH CH CH C CH N CH N CH OMe absent 192 CH₂ 1 N CH CH CH CH C CHN CH N CH OMe 193 S 1 N CH CH CH CH C CH N CH N CH OMe 194 CH₂ 1 CH CHCH CH CH C CH CH N CH N absent OMe 195 CH₂ 1 N CH CH CH CH C CH CH N CHN OMe 196 S 1 N CH CH CH CH C CH CH N CH N OMe 197 CH₂ 1 CH CH CH CH CHC CH CH N CH CH absent OMe 198 CH₂ 1 N CH CH CH CH C CH CH N CH CH OMe199 S 1 N N CH CH CH C CH CH N CH CH OMe 200 CH₂ 1 CH N CH CH CH C CH CHCH CH CH OMe OMe 201 CH₂ 1 N N CH CH CH C CH CH CH CH CH OMe OMe 202 S 1N N CH CH CH C CH CH CH CH CH OMe OMe 203 CH₂ 1 CH N CH CH CH C N N CHCH CH OMe OMe 204 CH2 1 N N CH CH CH C N CH CH CH CH OMe OMe 205 S 1 N NCH CH CH C N CH CH CH CH OMe OMe 206 CH₂ 1 CH N CH CH CH C CH N CH CH CHOMe OMe 207 CH₂ 1 N N CH CH CH C CH N CH CH CH OMe OMe 208 S 1 N N CH CHCH C CH N CH CH CH OMe OMe 209 CH₂ 1 CH N CH CH CH C N CH CH CH N OMeOMe 210 CH₂ 1 N N CH CH CH C N CH CH CH N OMe OMe 211 S 1 N N CH CH CH CN CH CH CH N OMe OMe 212 CH₂ 1 CH N CH CH CH C CH CH N CH N absent OMe213 CH₂ 1 N N CH CH CH C CH CH N CH N OMe 214 S 1 N N CH CH CH C CH CH NCH N OMe 215 CH₂ 1 CH N CH CH CH C N CH CH CH CH OMe OMe 216 CH₂ 1 N NCH CH CH C N CH CH CH CH OMe OMe 217 S 1 N N CH CH CH C N CH CH CH CHOMe OMe 218 CH₂ 1 CH N N CH CH C CH CH N CH N absent OMe 219 CH₂ 1 N N NCH CH C CH CH N CH N OMe 220 S 1 N N N CH CH C CH CH N CH N OMe 221 CH₂1 CH N N CH CH C CH CH CH CH CH OMe OMe 222 CH₂ 1 N N N CH CH C CH CH CHCH CH OMe OMe 223 S 1 N N N CH CH C CH CH CH CH CH OMe OMe 224 CH₂ 1 CHCH N CH CH C CH CH CH CH CH OMe OMe 225 CH₂ 1 N CH N CH CH C CH CH CH CHCH OMe OMe 226 S 1 N CH N CH CH C CH CH CH CH CH OMe OMe 227 CH₂ 1 CH CHN CH CH C N CH CH CH CH OMe OMe 228 CH₂ 1 N CH N CH CH C N CH CH CH CHOMe OMe 229 S 1 N CH N CH CH C N CH CH CH CH OMe OMe 230 CH₂ 1 CH CH NCH CH C CH N CH CH CH OMe OMe 231 CH₂ 1 N CH N CH CH C CH N CH CH CH OMeOMe 232 S 1 N CH N CH CH C CH N CH CH CH OMe OMe 233 CH₂ 1 CH CH N CH CHC CH N CH N CH OMe absent 234 CH₂ 1 N CH N CH CH C CH N CH N CH OMe 235S 1 N CH N CH CH C CH N CH N CH OMe 236 CH₂ 1 CH CH N CH CH C N CH CH NCH OMe OMe 237 CH₂ 1 N CH N CH CH C N CH CH N CH OMe OMe 238 S 1 N CH NCH CH C N CH CH N CH OMe OMe 239 CH₂ 1 CH CH N CH CH C CH CH N CH Nabsent OMe 240 CH₂ 1 N CH N CH CH C CH CH N CH N OMe 241 S 1 N CH N CHCH C CH CH N CH N OMe 242 CH₂ 1 CH CH N CH CH C CH CH N CH CH absent OMe243 CH₂ 1 N CH N CH CH C CH CH N CH CH OMe 244 S 1 N CH N CH CH C CH CHN CH CH OMe 245 CH₂ 1 CH N CH N CH C CH CH CH CH CH OMe OMe 246 CH₂ 1 NN CH N CH C CH CH CH CH CH OMe OMe 247 S 1 N N CH N CH C CH CH CH CH CHOMe OMe 248 CH₂ 1 CH N CH N CH C N CH CH CH CH OMe OMe 249 CH₂ 1 N N CHN CH C N CH CH CH CH OMe OMe 250 S 1 N N CH N CH C N CH CH CH CH OMe OMe251 CH₂ 1 CH N CH N CH C CH N CH CH CH OMe OMe 252 CH₂ 1 N N CH N CH CCH N CH CH CH OMe OMe 253 S 1 N N CH N CH C CH N CH CH CH OMe OMe 254CH₂ 1 CH CH N CH N C CH CH CH CH CH OMe OMe 255 CH₂ 1 N CH N CH N C CHCH CH CH CH OMe OMe 256 S 1 N CH N CH N C CH CH CH CH CH OMe OMe 257 CH₂1 CH CH CH N N C CH CH CH CH CH OMe OMe 258 CH₂ 1 N CH CH N N C CH CH CHCH CH OMe OMe 259 S 1 N CH CH N N C CH CH CH CH CH OMe OMe 260 CH₂ 1 CHCH CH CH N C CH CH CH CH CH OMe OMe 261 CH₂ 1 N CH CH CH N C CH CH CH CHCH OMe OMe 262 S 1 N CH CH CH N C CH CH CH CH CH OMe OMe 263 CH₂ 1 CH CHCH CH N C CH CH N CH CH absent OMe 264 CH₂ 1 N CH CH CH N C CH CH N CHCH OMe 265 S 1 N CH CH CH N C CH CH N CH CH OMe

In a further embodiment, the present invention provides compounds offormula (IIIa) and (IIIb), wherein X₁, n, Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇,Y₈, Y₉, Y₁₀, R₅, and R₆ are as defined in examples 266 to 443:

Comp X₁ n Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆ 266 CH₂ 1 CH CH CH CH CCH CH CH CH CH H H 267 S 1 CH CH CH CH C CH CH CH CH CH H H 268 CH₂ 1 CHCH CH CH C N CH CH CH CH H H 269 S 1 CH CH CH CH C N CH CH CH CH H H 270CH₂ 1 CH CH CH CH C CH N CH CH CH H H 271 S 1 CH CH CH CH C CH N CH CHCH H H 272 CH₂ 1 CH CH CH CH C N CH CH CH N H H 273 S 1 CH CH CH CH C NCH CH CH N H H 274 CH₂ 1 CH CH CH CH C N N CH CH CH H H 275 S 1 CH CH CHCH C N N CH CH CH H H 276 CH₂ 1 CH CH CH CH C CH N CH N CH H absent 277S 1 CH CH CH CH C CH N CH N CH H 278 CH₂ 1 CH CH CH CH C CH CH N CH Nabsent H 279 S 1 CH CH CH CH C CH CH N CH N H 280 CH₂ 1 CH CH CH CH C CHCH N CH CH absent H 281 S 1 CH CH CH CH C CH CH N CH CH H 282 CH₂ 1 N CHCH CH C CH CH CH CH CH H H 283 S 1 N CH CH CH C CH CH CH CH CH H H 284CH₂ 1 N CH CH CH C N CH CH CH CH H H 285 S 1 N CH CH CH C N CH CH CH CHH H 286 CH₂ 1 N CH CH CH C CH N CH CH CH H H 287 CH₂ 1 N CH CH CH C CH NCH CH CH H H 288 S 1 N CH CH CH C CH N CH CH CH H H 289 CH₂ 1 N CH CH CHC N CH CH CH N H H 290 S 1 N CH CH CH C N CH CH CH N H H 291 CH₂ 1 N CHCH CH C CH CH N CH N absent H 292 S 1 N CH CH CH C CH CH N CH N H 293CH₂ 1 N CH CH CH C N CH CH CH CH H H 294 S 1 N CH CH CH C N CH CH CH CHH H 295 CH₂ 1 N N CH CH C CH CH N CH N absent H 296 CH₂ 1 N N CH CH C CHCH N CH N H 297 S 1 N N CH CH C CH CH N CH N H 298 CH₂ 1 N N CH CH C CHCH CH CH CH H H 299 S 1 N N CH CH C CH CH CH CH CH H H 300 CH₂ 1 CH N CHCH C CH CH CH CH CH H H 301 S 1 CH N CH CH C CH CH CH CH CH H H 302 CH₂1 CH N CH CH C N CH CH CH CH H H 303 S 1 CH N CH CH C N CH CH CH CH H H304 CH₂ 1 CH N CH CH C CH N CH CH CH H H 305 S 1 CH N CH CH C CH N CH CHCH H H 306 CH₂ 1 CH N CH CH C CH N CH N CH H absent 307 S 1 CH N CH CH CCH N CH N CH H 308 CH₂ 1 CH N CH CH C N CH CH N CH H H 309 S 1 CH N CHCH C N CH CH N CH H H 310 CH₂ 1 CH N CH CH C CH CH N CH N absent H 311 S1 CH N CH CH C CH CH N CH N H 312 CH₂ 1 CH N CH CH C CH CH N CH CHabsent H 313 S 1 CH N CH CH C CH CH N CH CH H 314 CH₂ 1 N CH N CH C CHCH CH CH CH H H 315 S 1 N CH N CH C CH CH CH CH CH H H 316 CH₂ 1 N CH NCH C N CH CH CH CH H H 317 S 1 N CH N CH C N CH CH CH CH H H 318 CH₂ 1 NCH N CH C CH N CH CH CH H H 319 S 1 N CH N CH C CH N CH CH CH H H 320CH₂ 1 CH N CH N C CH CH CH CH CH H H 321 S 1 CH N CH N C CH CH CH CH CHH H 322 CH₂ 1 CH CH N N C CH CH CH CH CH H H 323 S 1 CH CH N N C CH CHCH CH CH H H 324 CH₂ 1 CH CH CH N C CH CH CH CH CH H H 325 S 1 CH CH CHN C CH CH CH CH CH H H 326 CH₂ 1 CH CH CH N C CH CH N CH CH absent H 327S 1 CH CH CH N C CH CH N CH CH H 328 CH₂ 1 CH CH CH CH C CH CH CH CH CHF H 329 s 1 CH CH CH CH C CH CH CH CH CH F H 330 CH₂ 1 CH CH CH CH C NCH CH CH CH F H 331 S 1 CH CH CH CH C N CH CH CH CH F H 332 CH₂ 1 CH CHCH CH C CH N CH CH CH F H 333 S 1 CH CH CH CH C CH N CH CH CH F H 334CH₂ 1 CH CH CH CH C N CH CH CH N F H 335 S 1 CH CH CH CH C N CH CH CH NF H 336 CH₂ 1 CH CH CH CH C N N CH CH CH F H 337 S 1 CH CH CH CH C N NCH CH CH F H 338 CH₂ 1 CH CH CH CH C CH N CH N CH F absent 339 S 1 CH CHCH CH C CH N CH N CH F 340 CH₂ 1 CH CH CH CH C CH CH N CH N absent 341 S1 CH CH CH CH C CH CH N CH N 342 CH₂ 1 CH CH CH CH C CH CH N CH CHabsent H 343 S 1 CH CH CH CH C CH CH N CH CH H 344 CH₂ 1 N CH CH CH C CHCH CH CH CH F H 345 S 1 N CH CH CH C CH CH CH CH CH F H 346 CH₂ 1 N CHCH CH C N CH CH CH CH F H 347 S 1 N CH CH CH C N CH CH CH CH F H 348 CH₂1 N CH CH CH C CH N CH CH CH F H 349 S 1 N CH CH CH C CH N CH CH CH F H350 CH₂ 1 N CH CH CH C N CH CH CH N F H 351 S 1 N CH CH CH C N CH CH CHN F H 352 CH₂ 1 N CH CH CH C CH CH N CH N absent H 353 S 1 N CH CH CH CCH CH N CH N H 354 CH₂ 1 N N CH CH C CH CH CH CH CH F H 355 S 1 N N CHCH C CH CH CH CH CH F H 356 CH₂ 1 N N CH CH C CH CH N CH N absent H 357S 1 N N CH CH C CH CH N CH N H 358 CH₂ 1 CH N CH CH C CH CH CH CH CH F H359 S 1 CH N CH CH C CH CH CH CH CH F H 360 CH₂ 1 CH N CH CH C N CH CHCH CH F H 361 S 1 CH N CH CH C N CH CH CH CH F H 362 CH₂ 1 CH N CH CH CCH N CH CH CH F H 363 S 1 CH N CH CH C CH N CH CH CH F H 364 CH₂ 1 CH NCH CH C CH N CH N CH F absent 365 S 1 CH N CH CH C CH N CH N CH F 366CH₂ 1 CH N CH CH C N CH CH N CH F absent 367 s 1 CH N CH CH C N CH CH NCH F 368 CH₂ 1 CH N CH CH C CH CH N CH N absent H 369 S 1 CH N CH CH CCH CH N CH N H 370 CH₂ 1 N CH N CH C CH CH CH CH CH F H 371 S 1 N CH NCH C CH CH CH CH CH F H 372 CH₂ 1 N CH N CH C N CH CH CH CH F H 373 S 1N CH N CH C N CH CH CH CH F H 374 CH₂ 1 N CH N CH C CH N CH CH CH F H375 S 1 N CH N CH C CH N CH CH CH F H 376 CH₂ 1 CH N CH N C CH CH CH CHCH F H 377 S 1 CH N CH N C CH CH CH CH CH F H 378 CH₂ 1 CH CH N N C CHCH CH CH CH F H 379 S 1 CH CH N N C CH CH CH CH CH F H 380 CH₂ 1 CH CHCH N C CH CH CH CH CH F H 381 S 1 CH CH CH N C CH CH CH CH CH F H 382CH₂ 1 CH CH CH N C CH N CH CH CH F H 383 S 1 CH CH CH N C CH N CH CH CHF H 384 CH₂ 1 CH CH CH CH C CH CH CH CH CH OMe OMe 385 S 1 CH CH CH CH CCH CH CH CH CH OMe OMe 386 CH₂ 1 CH CH CH CH C N CH CH CH CH OMe OMe 387S 1 CH CH CH CH C N CH CH CH CH OMe OMe 388 CH₂ 1 CH CH CH CH C CH N CHCH CH OMe OMe 389 S 1 CH CH CH CH C CH N CH CH CH OMe OMe 390 CH₂ 1 CHCH CH CH C N CH CH CH N OMe OMe 391 S 1 CH CH CH CH C N CH CH CH N OMeOMe 392 CH₂ 1 CH CH CH CH C N N CH CH CH OMe OMe 393 S 1 CH CH CH CH C NN CH CH CH OMe OMe 394 CH₂ 1 CH CH CH CH C CH N CH N CH OMe absent 395 S1 CH CH CH CH C CH N CH N CH OMe 396 CH₂ 1 CH CH CH CH C CH CH N CH Nabsent OMe 397 S 1 CH CH CH CH C CH CH N CH N OMe 398 CH₂ 1 CH CH CH CHC CH CH N CH CH absent OMe 399 S 1 CH CH CH CH C CH CH N CH CH OMe 400CH₂ 1 N CH CH CH C CH CH CH CH CH OMe OMe 401 S 1 N CH CH CH C CH CH CHCH CH OMe OMe 402 CH₂ 1 N CH CH CH C N CH CH CH CH OMe OMe 403 S 1 N CHCH CH C N CH CH CH CH OMe OMe 404 CH₂ 1 N CH CH CH C CH N CH CH CH OMeOMe 405 S 1 N CH CH CH C CH N CH CH CH OMe OMe 406 CH₂ 1 N CH CH CH C NCH CH CH N OMe OMe 407 S 1 N CH CH CH C N CH CH CH N OMe OMe 408 CH₂ 1 NCH CH CH C CH CH N CH N absent OMe 409 S 1 N CH CH CH C CH CH N CH N OMe410 CH₂ 1 N CH CH CH C N CH CH CH CH OMe OMe 411 S 1 N CH CH CH C N CHCH CH CH OMe OMe 412 CH₂ 1 N N CH CH C CH CH N CH N absent OMe 413 S 1 NN CH CH C CH CH N CH N OMe 414 CH₂ 1 N N CH CH C CH CH CH CH CH OMe OMe415 S 1 N N CH CH C CH CH CH CH CH OMe OMe 416 CH₂ 1 CH N CH CH C CH CHCH CH CH OMe OMe 417 S 1 CH N CH CH C CH CH CH CH CH OMe OMe 418 CH₂ 1CH N CH CH C N CH CH CH CH OMe OMe 419 S 1 CH N CH CH C N CH CH CH CHOMe OMe 420 CH₂ 1 CH N CH CH C CH N CH CH CH OMe OMe 421 S 1 CH N CH CHC CH N CH CH CH OMe OMe 422 CH₂ 1 CH N CH CH C CH N CH N CH OMe absent423 S 1 CH N CH CH C CH N CH N CH OMe 424 CH₂ 1 CH N CH CH C N CH CH NCH OMe OMe 425 S 1 CH N CH CH C N CH CH N CH OMe OMe 426 CH₂ 1 CH N CHCH C CH CH N CH N absent OMe 427 S 1 CH N CH CH C CH CH N CH N OMe 428CH₂ 1 CH N CH CH C CH CH N CH CH OMe absent 429 S 1 CH N CH CH C CH CH NCH CH OMe 430 CH₂ 1 N CH N CH C CH CH CH CH CH OMe OMe 431 S 1 N CH N CHC CH CH CH CH CH OMe OMe 432 CH₂ 1 N CH N CH C N CH CH CH CH OMe OMe 433S 1 N CH N CH C N CH CH CH CH OMe OMe 434 CH₂ 1 N CH N CH C CH N CH CHCH OMe OMe 435 S 1 N CH N CH C CH N CH CH CH OMe OMe 436 CH₂ 1 CH N CH NC CH CH CH CH CH OMe OMe 437 S 1 CH N CH N C CH CH CH CH CH OMe OMe 438CH₂ 1 CH CH N N C CH CH CH CH CH OMe OMe 439 S 1 CH CH N N C CH CH CH CHCH OMe OMe 440 CH₂ 1 CH CH CH N C CH CH CH CH CH OMe OMe 441 S 1 CH CHCH N C CH CH CH CH CH OMe OMe 442 CH₂ 1 CH CH CH N C CH CH N CH CHabsent OMe 443 S 1 CH CH CH N C CH CH N CH CH OMe

In a further embodiment, the present invention provides compounds offormula (IVa) and (IVb), wherein X₁, o, Z, Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇,Y₈, Y₉, Y₁₀, R₅, and R₆ are as defined in examples 444 to 795:

In both, formulae (IVa) and (IVb), o is 0.

Comp p Z Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆ 444 0 CH CH CH CH CH C CHCH CH CH CH H H 445 0 N CH CH CH CH C CH CH CH CH CH H H 446 0 CH CH CHCH CH C N CH CH CH CH H H 447 0 N CH CH CH CH C N CH CH CH CH H H 448 0CH CH CH CH CH C CH N CH CH CH H H 449 0 N CH CH CH CH C CH N CH CH CH HH 450 0 CH CH CH CH CH C N CH CH CH N H H 451 0 N CH CH CH CH C N CH CHCH N H H 452 0 CH CH CH CH CH C N N CH CH CH H H 453 0 N CH CH CH CH C NN CH CH CH H H 454 0 CH CH CH CH CH C CH N CH N CH H absent 455 0 N CHCH CH CH C CH N CH N CH H 456 0 CH CH CH CH CH C CH CH N CH N absent H457 0 N CH CH CH CH C CH CH N CH N H 458 0 CH CH CH CH CH C CH CH N CHCH absent H 459 0 N CH CH CH CH C CH CH N CH CH H 460 0 CH N CH CH CH CCH CH CH CH CH H H 461 0 N N CH CH CH C CH CH CH CH CH H H 462 0 CH N CHCH CH C N CH CH CH CH H H 463 0 N N CH CH CH C N CH CH CH CH H H 464 0CH N CH CH CH C CH N CH CH CH H H 465 0 N N CH CH CH C CH N CH CH CH H H466 0 CH N CH CH CH C N CH CH CH N H H 467 0 N N CH CH CH C N CH CH CH NH H 468 0 CH N CH CH CH C CH CH N CH N absent H 469 0 N N CH CH CH C CHCH N CH N H 470 0 CH N CH CH CH C N CH CH CH CH H H 471 0 N N CH CH CH CN CH CH CH CH H H 472 0 CH N N CH CH C CH CH N CH N absent H 473 0 N N NCH CH C CH CH N CH N H 474 0 CH N N CH CH C CH CH CH CH CH H H 475 0 N NN CH CH C CH CH CH CH CH H H 476 0 CH CH N CH CH C CH CH CH CH CH H H477 0 N CH N CH CH C CH CH CH CH CH H H 478 0 CH CH N CH CH C N CH CH CHCH H H 479 0 N CH N CH CH C N CH CH CH CH H H 480 0 CH CH N CH CH C CH NCH CH CH H H 481 0 N CH N CH CH C CH N CH CH CH H H 482 0 CH CH N CH CHC CH N CH N CH H absent 483 0 N CH N CH CH C CH N CH N CH H 484 0 CH CHN CH CH C N CH CH N CH H H 485 0 N CH N CH CH C N CH CH N CH H H 486 0CH CH N CH CH C CH CH N CH N absent H 487 0 N CH N CH CH C CH CH N CH NH 488 0 CH CH N CH CH C CH CH N CH CH absent H 489 0 N CH N CH CH C CHCH N CH CH H 490 0 CH N CH N CH C CH CH CH CH CH H H 491 0 N N CH N CH CCH CH CH CH CH H H 492 0 CH N CH N CH C N CH CH CH CH H H 493 0 N N CH NCH C N CH CH CH CH H H 494 0 CH N CH N CH C CH N CH CH CH H H 495 0 N NCH N CH C CH N CH CH CH H H 496 0 CH CH N CH N C CH CH CH CH CH H H 4970 N CH N CH N C CH CH CH CH CH H H 498 0 CH CH CH N N C CH CH CH CH CH HH 499 0 N CH CH N N C CH CH CH CH CH H H 500 0 CH CH CH CH N C CH CH CHCH CH H H 501 0 N CH CH CH N C CH CH CH CH CH H H 502 0 CH CH CH CH N CCH CH N CH CH absent H 503 0 N CH CH CH N C CH CH N CH CH H 504 0 CH CHCH CH CH C CH CH CH CH CH F H 505 0 N CH CH CH CH C CH CH CH CH CH F H506 0 CH CH CH CH CH C N CH CH CH CH F H 507 0 N CH CH CH CH C N CH CHCH CH F H 508 0 CH CH CH CH CH C CH N CH CH CH F H 509 0 N CH CH CH CH CCH N CH CH CH F H 510 0 CH CH CH CH CH C N CH CH CH N F H 511 0 N CH CHCH CH C N CH CH CH N F H 512 0 CH CH CH CH CH C N N CH CH CH F H 513 0 NCH CH CH CH C N N CH CH CH F H 514 0 CH CH CH CH CH C CH N CH N CH Fabsent 515 0 N CH CH CH CH C CH N CH N CH F 516 0 CH CH CH CH CH C CH CHN CH N absent 517 0 N CH CH CH CH C CH CH N CH N 518 0 CH CH CH CH CH CCH CH N CH CH absent H 519 0 N CH CH CH CH C CH CH N CH CH H 520 0 CH NCH CH CH C CH CH CH CH CH F H 521 0 N N CH CH CH C CH CH CH CH CH F H522 0 CH N CH CH CH C N CH CH CH CH F H 523 0 N N CH CH CH C N CH CH CHCH F H 524 0 CH N CH CH CH C CH N CH CH CH F H 525 0 N N CH CH CH C CH NCH CH CH F H 526 0 CH N CH CH CH C N CH CH CH N F H 527 0 N N CH CH CH CN CH CH CH N F H 528 0 CH N CH CH CH C CH CH N CH N absent H 529 0 N NCH CH CH C CH CH N CH N H 530 0 CH N N CH CH C CH CH CH CH CH F H 531 0N N N CH CH C CH CH CH CH CH F H 532 0 CH N N CH CH C CH CH N CH Nabsent H 533 0 N N N CH CH C CH CH N CH N H 534 0 CH CH N CH CH C CH CHCH CH CH F H 535 0 N CH N CH CH C CH CH CH CH CH F H 536 0 CH CH N CH CHC N CH CH CH CH F H 537 0 N CH N CH CH C N CH CH CH CH F H 538 0 CH CH NCH CH C CH N CH CH CH F H 539 0 N CH N CH CH C CH N CH CH CH F H 540 0CH CH N CH CH C CH N CH N CH H absent 541 0 N CH N CH CH C CH N CH N CHF 542 0 CH CH N CH CH C N CH CH N CH F absent 543 0 N CH N CH CH C N CHCH N CH F 544 0 CH CH N CH CH C CH CH N CH N absent H 545 0 N CH N CH CHC CH CH N CH N H 546 0 CH N CH N CH C CH CH CH CH CH F H 547 0 N N CH NCH C CH CH CH CH CH F H 548 0 CH N CH N CH C N CH CH CH CH F H 549 0 N NCH N CH C N CH CH CH CH F H 550 0 CH N CH N CH C CH N CH CH CH F H 551 0N N CH N CH C CH N CH CH CH F H 552 0 CH CH N CH N C CH CH CH CH CH F H553 0 N CH N CH N C CH CH CH CH CH F H 554 0 CH CH CH N N C CH CH CH CHCH F H 555 0 N CH CH N N C CH CH CH CH CH F H 556 0 CH CH CH CH N C CHCH CH CH CH F H 557 0 N CH CH CH N C CH CH CH CH CH F H 558 0 CH CH CHCH N C CH N CH CH CH F H 559 0 N CH CH CH N C CH N CH CH CH F H 560 0 CHCH CH CH CH C CH CH CH CH CH OMe OMe 561 0 N CH CH CH CH C CH CH CH CHCH OMe OMe 562 0 CH CH CH CH CH C N CH CH CH CH OMe OMe 563 0 N CH CH CHCH C N CH CH CH CH OMe OMe 564 0 CH CH CH CH CH C CH N CH CH CH OMe OMe565 0 N CH CH CH CH C CH N CH CH CH OMe OMe 566 0 CH CH CH CH CH C N CHCH CH N OMe OMe 567 0 N CH CH CH CH C N CH CH CH N OMe OMe 568 0 CH CHCH CH CH C N N CH CH CH OMe OMe 569 0 N CH CH CH CH C N N CH CH CH OMeOMe 570 0 CH CH CH CH CH C CH N CH N CH OMe absent 571 0 N CH CH CH CH CCH N CH N CH OMe 572 0 CH CH CH CH CH C CH CH N CH N absent OMe 573 0 NCH CH CH CH C CH CH N CH N OMe 574 0 CH CH CH CH CH C CH CH N CH CHabsent OMe 575 0 N CH CH CH CH C CH CH N CH CH OMe 576 0 CH N CH CH CH CCH CH CH CH CH OMe OMe 577 0 N N CH CH CH C CH CH CH CH CH OMe OMe 578 0CH N CH CH CH C N CH CH CH CH OMe OMe 579 0 N N CH CH CH C N CH CH CH CHOMe OMe 580 0 CH N CH CH CH C CH N CH CH CH OMe OMe 581 0 N N CH CH CH CCH N CH CH CH OMe OMe 582 0 CH N CH CH CH C N CH CH CH N OMe OMe 583 0 NN CH CH CH C N CH CH CH N OMe OMe 584 0 CH N CH CH CH C CH CH N CH Nabsent OMe 585 0 N N CH CH CH C CH CH N CH N OMe 586 0 CH N CH CH CH C NCH CH CH CH OMe OMe 587 0 N N CH CH CH C N CH CH CH CH OMe OMe 588 0 CHN N CH CH C CH CH N CH N absent OMe 589 0 N N N CH CH C CH CH N CH N OMe590 0 CH N N CH CH C CH CH CH CH CH OMe OMe 591 0 N N N CH CH C CH CH CHCH CH OMe OMe 592 0 CH CH N CH CH C CH CH CH CH CH OMe OMe 593 0 N CH NCH CH C CH CH CH CH CH OMe OMe 594 0 CH CH N CH CH C N CH CH CH CH OMeOMe 595 0 N CH N CH CH C N CH CH CH CH OMe OMe 596 0 CH CH N CH CH C CHN CH CH CH OMe OMe 597 0 N CH N CH CH C CH N CH CH CH OMe OMe 598 0 CHCH N CH CH C CH N CH N CH OMe absent 599 0 N CH N CH CH C CH N CH N CHOMe 600 0 CH CH N CH CH C N CH CH N CH OMe OMe 601 0 N CH N CH CH C N CHCH N CH OMe OMe 602 0 CH CH N CH CH C CH CH N CH N absent OMe 603 0 N CHN CH CH C CH CH N CH N OMe 604 0 CH CH N CH CH C CH CH N CH CH absentOMe 605 0 N CH N CH CH C CH CH N CH CH OMe 606 0 CH N CH N CH C CH CH CHCH CH OMe OMe 607 0 N N CH N CH C CH CH CH CH CH OMe OMe 608 0 CH N CH NCH C N CH CH CH CH OMe OMe 609 0 N N CH N CH C N CH CH CH CH OMe OMe 6100 CH N CH N CH C CH N CH CH CH OMe OMe 611 0 N N CH N CH C CH N CH CH CHOMe OMe 612 0 CH CH N CH N C CH CH CH CH CH OMe OMe 613 0 N CH N CH N CCH CH CH CH CH OMe OMe 614 0 CH CH CH N N C CH CH CH CH CH OMe OMe 615 0N CH CH N N C CH CH CH CH CH OMe OMe 616 0 CH CH CH CH N C CH CH CH CHCH OMe OMe 617 0 N CH CH CH N C CH CH CH CH CH OMe OMe 618 0 CH CH CH CHN C CH CH N CH CH absent OMe 619 0 N CH CH CH N C CH CH N CH CH OMe 6201 CH CH CH CH CH C CH CH CH CH CH H H 621 1 N CH CH CH CH C CH CH CH CHCH H H 622 1 CH CH CH CH CH C N CH CH CH CH H H 623 1 N CH CH CH CH C NCH CH CH CH H H 624 1 CH CH CH CH CH C CH N CH CH CH H H 625 1 N CH CHCH CH C CH N CH CH CH H H 626 1 CH CH CH CH CH C N CH CH CH N H H 627 1N CH CH CH CH C N CH CH CH N H H 628 1 CH CH CH CH CH C N N CH CH CH H H629 1 N CH CH CH CH C N N CH CH CH H H 630 1 CH CH CH CH CH C CH N CH NCH H absent 631 1 N CH CH CH CH C CH N CH N CH H 632 1 CH CH CH CH CH CCH CH N CH N absent H 633 1 N CH CH CH CH C CH CH N CH N H 634 1 CH CHCH CH CH C CH CH N CH CH absent H 635 1 N CH CH CH CH C CH CH N CH CH H636 1 CH N CH CH CH C CH CH CH CH CH H H 637 1 N N CH CH CH C CH CH CHCH CH H H 638 1 CH N CH CH CH C N CH CH CH CH H H 639 1 N N CH CH CH C NCH CH CH CH H H 640 1 CH N CH CH CH C CH N CH CH CH H H 641 1 N N CH CHCH C CH N CH CH CH H H 642 1 CH N CH CH CH C N CH CH CH N H H 643 1 N NCH CH CH C N CH CH CH N H H 644 1 CH N CH CH CH C CH CH N CH N absent H645 1 N N CH CH CH C CH CH N CH N H 646 1 CH N CH CH CH C N CH CH CH CHH H 647 1 N N CH CH CH C N CH CH CH CH H H 648 1 CH N N CH CH C CH CH NCH N absent H 649 1 N N N CH CH C CH CH N CH N H 650 1 CH N N CH CH C CHCH CH CH CH H H 651 1 N N N CH CH C CH CH CH CH CH H H 652 1 CH CH N CHCH C CH CH CH CH CH H H 653 1 N CH N CH CH C CH CH CH CH CH H H 654 1 CHCH N CH CH C N CH CH CH CH H H 655 1 N CH N CH CH C N CH CH CH CH H H656 1 CH CH N CH CH C CH N CH CH CH H H 657 1 N CH N CH CH C CH N CH CHCH H H 658 1 CH CH N CH CH C CH N CH N CH H absent 659 1 N CH N CH CH CCH N CH N CH H 660 1 CH CH N CH CH C N CH CH N CH H H 661 1 N CH N CH CHC N CH CH N CH H H 662 1 CH CH N CH CH C CH CH N CH N absent H 663 1 NCH N CH CH C CH CH N CH N H 664 1 CH CH N CH CH C CH CH N CH CH absent H665 1 N CH N CH CH C CH CH N CH CH H 666 1 CH N CH N CH C CH CH CH CH CHH H 667 1 N N CH N CH C CH CH CH CH CH H H 668 1 CH N CH N CH C N CH CHCH CH H H 669 1 N N CH N CH C N CH CH CH CH H H 670 1 CH N CH N CH C CHN CH CH CH H H 671 1 N N CH N CH C CH N CH CH CH H H 672 1 CH CH N CH NC CH CH CH CH CH H H 673 1 N CH N CH N C CH CH CH CH CH H H 674 1 CH CHCH N N C CH CH CH CH CH H H 675 1 N CH CH N N C CH CH CH CH CH H H 676 1CH CH CH CH N C CH CH CH CH CH H H 677 1 N CH CH CH N C CH CH CH CH CH HH 678 1 CH CH CH CH N C CH CH N CH CH absent H 679 1 N CH CH CH N C CHCH N CH CH H 680 1 CH CH CH CH CH C CH CH CH CH CH F H 681 1 N CH CH CHCH C CH CH CH CH CH F H 682 1 CH CH CH CH CH C N CH CH CH CH F H 683 1 NCH CH CH CH C N CH CH CH CH F H 684 1 CH CH CH CH CH C CH N CH CH CH F H685 1 N CH CH CH CH C CH N CH CH CH F H 686 1 CH CH CH CH CH C N CH CHCH N F H 687 1 N CH CH CH CH C N CH CH CH N F H 688 1 CH CH CH CH CH C NN CH CH CH F H 689 1 N CH CH CH CH C N N CH CH CH F H 690 1 CH CH CH CHCH C CH N CH N CH F absent 691 1 N CH CH CH CH C CH N CH N CH F 692 1 CHCH CH CH CH C CH CH N CH N absent 693 1 N CH CH CH CH C CH CH N CH N 6941 CH CH CH CH CH C CH CH N CH CH absent H 695 1 N CH CH CH CH C CH CH NCH CH H 696 1 CH N CH CH CH C CH CH CH CH CH F H 697 1 N N CH CH CH C CHCH CH CH CH F H 698 1 CH N CH CH CH C N CH CH CH CH F H 699 1 N N CH CHCH C N CH CH CH CH F H 700 1 CH N CH CH CH C CH N CH CH CH F H 701 1 N NCH CH CH C CH N CH CH CH F H 702 1 CH N CH CH CH C N CH CH CH N F H 7031 N N CH CH CH C N CH CH CH N F H 704 1 CH N CH CH CH C CH CH N CH Nabsent H 705 1 N N CH CH CH C CH CH N CH N H 706 1 CH N N CH CH C CH CHCH CH CH F H 707 1 N N N CH CH C CH CH CH CH CH F H 708 1 CH N N CH CH CCH CH N CH N absent H 709 1 N N N CH CH C CH CH N CH N H 710 1 CH CH NCH CH C CH CH CH CH CH F H 711 1 N CH N CH CH C CH CH CH CH CH F H 712 1CH CH N CH CH C N CH CH CH CH F H 713 1 N CH N CH CH C N CH CH CH CH F H714 1 CH CH N CH CH C CH N CH CH CH F H 715 1 N CH N CH CH C CH N CH CHCH F H 716 1 CH CH N CH CH C CH N CH N CH F absent 717 1 N CH N CH CH CCH N CH N CH F 718 1 CH CH N CH CH C N CH CH N CH F absent 719 1 N CH NCH CH C N CH CH N CH F 720 1 CH CH N CH CH C CH CH N N absent H 721 1 NCH N CH CH C CH CH N N H 722 1 CH N CH N CH C CH CH CH CH CH F H 723 1 NN CH N CH C CH CH CH CH CH F H 724 1 CH N CH N CH C N CH CH CH CH F H725 1 N N CH N CH C N CH CH CH CH F H 726 1 CH N CH N CH C CH N CH CH CHF H 727 1 N N CH N CH C CH N CH CH CH F H 728 1 CH CH N CH N C CH CH CHCH CH F H 729 1 N CH N CH N C CH CH CH CH CH F H 730 1 CH CH CH N N C CHCH CH CH CH F H 731 1 N CH CH N N C CH CH CH CH CH F H 732 1 CH CH CH CHN C CH CH CH CH CH F H 733 1 N CH CH CH N C CH CH CH CH CH F H 734 1 CHCH CH CH N C CH N CH CH CH F H 735 1 N CH CH CH N C CH N CH CH CH F H736 1 CH CH CH CH CH C CH CH CH CH CH OMe OMe 737 1 N CH CH CH CH C CHCH CH CH CH OMe OMe 738 1 CH CH CH CH CH C N CH CH CH CH OMe OMe 739 1 NCH CH CH CH C N CH CH CH CH OMe OMe 740 1 CH CH CH CH CH C CH N CH CH CHOMe OMe 741 1 N CH CH CH CH C CH N CH CH CH OMe OMe 742 1 CH CH CH CH CHC N CH CH CH N OMe OMe 743 1 N CH CH CH CH C N CH CH CH N OMe OMe 744 1CH CH CH CH CH C N N CH CH CH OMe OMe 745 1 N CH CH CH CH C N N CH CH CHOMe OMe 746 1 CH CH CH CH CH C CH N CH N CH OMe absent 747 1 N CH CH CHCH C CH N CH N CH OMe 748 1 CH CH CH CH CH C CH CH N CH N absent OMe 7491 N CH CH CH CH C CH CH N CH N OMe 750 1 CH CH CH CH CH C CH CH N CH CHabsent OMe 751 1 N CH CH CH CH C CH CH N CH CH OMe 752 1 CH N CH CH CH CCH CH CH CH CH OMe OMe 753 1 N N CH CH CH C CH CH CH CH CH OMe OMe 754 1CH N CH CH CH C N CH CH CH CH OMe OMe 755 1 N N CH CH CH C N CH CH CH CHOMe OMe 756 1 CH N CH CH CH C CH N CH CH CH OMe OMe 757 1 N N CH CH CH CCH N CH CH CH OMe OMe 758 1 CH N CH CH CH C N CH CH CH N OMe OMe 759 1 NN CH CH CH C N CH CH CH N OMe OMe 760 1 CH N CH CH CH C CH CH N CH Nabsent OMe 761 1 N N CH CH CH C CH CH N CH N OMe 762 1 CH N CH CH CH C NCH CH CH CH OMe OMe 763 1 N N CH CH CH C N CH CH CH CH OMe OMe 764 1 CHN N CH CH C CH CH N CH N absent OMe 765 1 N N N CH CH C CH CH N CH N OMe766 1 CH N N CH CH C CH CH CH CH CH OMe OMe 767 1 N N N CH CH C CH CH CHCH CH OMe OMe 768 1 CH CH N CH CH C CH CH CH CH CH OMe OMe 769 1 N CH NCH CH C CH CH CH CH CH OMe OMe 770 1 CH CH N CH CH C N CH CH CH CH OMeOMe 771 1 N CH N CH CH C N CH CH CH CH OMe OMe 772 1 CH CH N CH CH C CHN CH CH CH OMe OMe 773 1 N CH N CH CH C CH N CH CH CH OMe OMe 774 1 CHCH N CH CH C CH N CH N CH OMe absent 775 1 N CH N CH CH C CH N CH N CHOMe 776 1 CH CH N CH CH C N CH CH N CH OMe OMe 777 1 N CH N CH CH C N CHCH N CH OMe OMe 778 1 CH CH N CH CH C CH CH N CH N absent OMe 779 1 N CHN CH CH C CH CH N CH N OMe 780 1 CH CH N CH CH C CH CH N CH CH absentOMe 781 1 N CH N CH CH C CH CH N CH CH OMe 782 1 CH N CH N CH C CH CH CHCH CH OMe OMe 783 1 N N CH N CH C CH CH CH CH CH OMe OMe 784 1 CH N CH NCH C N CH CH CH CH OMe OMe 785 1 N N CH N CH C N CH CH CH CH OMe OMe 7861 CH N CH N CH C CH N CH CH CH OMe OMe 787 1 N N CH N CH C CH N CH CH CHOMe OMe 788 1 CH CH N CH N C CH CH CH CH CH OMe OMe 789 1 N CH N CH N CCH CH CH CH CH OMe OMe 790 1 CH CH CH N N C CH CH CH CH CH OMe OMe 791 1N CH CH N N C CH CH CH CH CH OMe OMe 792 1 CH CH CH CH N C CH CH CH CHCH OMe OMe 793 1 N CH CH CH N C CH CH CH CH CH OMe OMe 794 1 CH CH CH CHN C CH CH N CH CH absent OMe 795 1 N CH CH CH N C CH CH N CH CH OMe

In a further embodiment, the present invention provides compounds offormula (IVa) and (IVb), wherein X₁, o, Z, Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇,Y₈, Y₉, Y₁₀, R₅, and R₆ are as defined in examples 1289 to 1296:

In both, formulae (IVa) and (IVb), o is 0.

Comp p Z Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆ 1289 0 N CH CH CH CH C CHCH CH CH CH OMe H 1290 0 N N CH CH CH C CH CH CH CH CH OMe H 1291 0 N CHCH N CH C CH CH CH CH CH OMe H 1292 0 N CH CH N CH C CH CH CH CH CH OMeOMe 1293 0 N N CH CH N C CH CH CH CH CH F H 1294 0 N CH CH CH C CH CH CHCH CH CH O-Phenyl H 1295 0 N CH CH CH CH C CH CH CH CH CH propoxy H 12960 N CH CH CH CH C CH CH CH CH CH propan-2-yloxy H

In a further embodiment, the present invention provides compounds offormula (Va) and (Vb), wherein o, Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈, Y₉,Y₁₀, R₅, and R₆ are as defined in examples 796 to 971:

In both, formulae (Va) and (Vb), o is 0.

Comp p Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆ 796 0 CH CH CH CH C CH CH CHCH CH H H 797 0 CH CH CH CH C N CH CH CH CH H H 798 0 CH CH CH CH C CH NCH CH CH H H 799 0 CH CH CH CH C N CH CH CH N H H 800 0 CH CH CH CH C NN CH CH CH H H 801 0 CH CH CH CH C CH N CH N CH H absent 802 0 CH CH CHCH C CH CH N CH N absent H 803 0 CH CH CH CH C CH CH N CH CH absent H804 0 N CH CH CH C CH CH CH CH CH H H 805 0 N CH CH CH C N CH CH CH CH HH 806 0 N CH CH CH C CH N CH CH CH H H 807 0 N CH CH CH C N CH CH CH N HH 808 0 N CH CH CH C CH CH N CH N absent H 809 0 N CH CH CH C N CH CH CHCH H H 810 0 N N CH CH C CH CH N CH N absent H 811 0 N N CH CH C CH CHCH CH CH H H 812 0 CH N CH CH C CH CH CH CH CH H H 813 0 CH N CH CH C NCH CH CH CH H H 814 0 CH N CH CH C CH N CH CH CH H H 815 0 CH N CH CH CCH N CH N CH H absent 816 0 CH N CH CH C N CH CH N CH H H 817 0 CH N CHCH C CH CH N CH N absent H 818 0 CH N CH CH C CH CH N CH CH absent H 8190 N CH N CH C CH CH CH CH CH H H 820 0 N CH N CH C N CH CH CH CH H H 8210 N CH N CH C CH N CH CH CH H H 822 0 CH N CH N C CH CH CH CH CH H H 8230 CH CH N N C CH CH CH CH CH H H 824 0 CH CH CH N C CH CH CH CH CH H H825 0 CH CH CH N C CH CH N CH CH absent H 826 0 CH CH CH CH C CH CH CHCH CH F H 827 0 CH CH CH CH C N CH CH CH CH F H 828 0 CH CH CH CH C CH NCH CH CH F H 829 0 CH CH CH CH C N CH CH CH N F H 830 0 CH CH CH CH C NN CH CH CH F H 831 0 CH CH CH CH C CH N CH N CH F absent 832 0 CH CH CHCH C CH CH N CH N absent 833 0 CH CH CH CH C CH CH N CH CH absent H 8340 N CH CH CH C CH CH CH CH CH F H 835 0 N CH CH CH C N CH CH CH CH F H836 0 N CH CH CH C CH N CH CH CH F H 837 0 N CH CH CH C N CH CH CH N F H838 0 N CH CH CH C CH CH N CH N absent H 839 0 N N CH CH C CH CH CH CHCH F H 840 0 N N CH CH C CH CH N CH N absent H 841 0 CH N CH CH C CH CHCH CH CH F H 842 0 CH N CH CH C N CH CH CH CH F H 843 0 CH N CH CH C CHN CH CH CH F H 844 0 CH N CH CH C CH N CH N CH F absent 845 0 CH N CH CHC N CH CH N CH F absent 846 0 CH N CH CH C CH CH N CH N absent H 847 0 NCH N CH C CH CH CH CH CH F H 848 0 N CH N CH C N CH CH CH CH F H 849 0 NCH N CH C CH N CH CH CH F H 850 0 CH N CH N C CH CH CH CH CH F H 851 0CH CH N N C CH CH CH CH CH F H 852 0 CH CH CH N C CH CH CH CH CH F H 8530 CH CH CH N C CH N CH CH CH F H 854 0 CH CH CH CH C CH CH CH CH CH OMeOMe 855 0 CH CH CH CH C N CH CH CH CH OMe OMe 856 0 CH CH CH CH C CH NCH CH CH OMe OMe 857 0 CH CH CH CH C N CH CH CH N OMe OMe 858 0 CH CH CHCH C N N CH CH CH OMe OMe 859 0 CH CH CH CH C CH N CH N CH OMe absent860 0 CH CH CH CH C CH CH N CH N absent OMe 861 0 CH CH CH CH C CH CH NCH CH absent OMe 862 0 N CH CH CH C CH CH CH CH CH OMe OMe 863 0 N CH CHCH C N CH CH CH CH OMe OMe 864 0 N CH CH CH C CH N CH CH CH OMe OMe 8650 N CH CH CH C N CH CH CH N OMe OMe 866 0 N CH CH CH C CH CH N CH Nabsent OMe 867 0 N CH CH CH C N CH CH CH CH OMe OMe 868 0 N N CH CH C CHCH N CH N absent OMe 869 0 N N CH CH C CH CH CH CH CH OMe OMe 870 0 CH NCH CH C CH CH CH CH CH OMe OMe 871 0 CH N CH CH C N CH CH CH CH OMe OMe872 0 CH N CH CH C CH N CH CH CH OMe OMe 873 0 CH N CH CH C CH N CH N CHOMe absent 874 0 CH N CH CH C N CH CH N CH OMe OMe 875 0 CH N CH CH C CHCH N CH N absent OMe 876 0 CH N CH CH C CH CH N CH CH absent OMe 877 0 NCH N CH C CH CH CH CH CH OMe OMe 878 0 N CH N CH C N CH CH CH CH OMe OMe879 0 N CH N CH C CH N CH CH CH OMe OMe 880 0 CH N CH N C CH CH CH CH CHOMe OMe 881 0 CH CH N N C CH CH CH CH CH OMe OMe 882 0 CH CH CH N C CHCH CH CH CH OMe OMe 883 0 CH CH CH N C CH CH N CH CH absent OMe 884 1 CHCH CH CH C CH CH CH CH CH H H 885 1 CH CH CH CH C N CH CH CH CH H H 8861 CH CH CH CH C CH N CH CH CH H H 887 1 CH CH CH CH C N CH CH CH N H H888 1 CH CH CH CH C N N CH CH CH H H 889 1 CH CH CH CH C CH N CH N CH Habsent 890 1 CH CH CH CH C CH CH N CH N absent H 891 1 CH CH CH CH C CHCH N CH CH absent H 892 1 N CH CH CH C CH CH CH CH CH H H 893 1 N CH CHCH C N CH CH CH CH H H 894 1 N CH CH CH C CH N CH CH CH H H 895 1 N CHCH CH C N CH CH CH N H H 896 1 N CH CH CH C CH CH N CH N absent H 897 1N CH CH CH C N CH CH CH CH H H 898 1 N N CH CH C CH CH N CH N absent H899 1 N N CH CH C CH CH CH CH CH H H 900 1 CH N CH CH C CH CH CH CH CH HH 901 1 CH N CH CH C N CH CH CH CH H H 902 1 CH N CH CH C CH N CH CH CHH H 903 1 CH N CH CH C CH N CH N CH H absent 904 1 CH N CH CH C N CH CHN CH H H 905 1 CH N CH CH C CH CH N CH N absent H 906 1 CH N CH CH C CHCH N CH CH absent H 907 1 N CH N CH C CH CH CH CH CH H H 908 1 N CH N CHC N CH CH CH CH H H 909 1 N CH N CH C CH N CH CH CH H H 910 1 CH N CH NC CH CH CH CH CH H H 911 1 CH CH N N C CH CH CH CH CH H H 912 1 CH CH CHN C CH CH CH CH CH H H 913 1 CH CH CH N C CH CH N CH CH absent H 914 1CH CH CH CH C CH CH CH CH CH F H 915 1 CH CH CH CH C N CH CH CH CH F H916 1 CH CH CH CH C CH N CH CH CH F H 917 1 CH CH CH CH C N CH CH CH N FH 918 1 CH CH CH CH C N N CH CH CH F H 919 1 CH CH CH CH C CH N CH N Fabsent 920 1 CH CH CH CH C CH CH N CH N absent 921 1 CH CH CH CH C CH CHN CH CH absent H 922 1 N CH CH CH C CH CH CH CH CH F H 923 1 N CH CH CHC N CH CH CH CH F H 924 1 N CH CH CH C CH N CH CH CH F H 925 1 N CH CHCH C N CH CH CH N F H 926 1 N CH CH CH C CH CH N CH N absent H 927 1 N NCH CH C CH CH CH CH CH F H 928 1 N N CH CH C CH CH N CH N absent H 929 1CH N CH CH C CH CH CH CH CH F H 930 1 CH N CH CH C N CH CH CH CH F H 9311 CH N CH CH C CH N CH CH CH F H 932 1 CH N CH CH C CH N CH N CH Fabsent 933 1 CH N CH CH C N CH CH N CH F absent 934 1 CH N CH CH C CH CHN CH N absent H 935 1 N CH N CH C CH CH CH CH CH F H 936 1 N CH N CH C NCH CH CH CH F H 937 1 N CH N CH C CH N CH CH CH F H 938 1 CH N CH N C CHCH CH CH CH F H 939 1 CH CH N N C CH CH CH CH CH F H 940 1 CH CH CH N CCH CH CH CH CH F H 941 1 CH CH CH N C CH N CH CH CH F H 942 1 CH CH CHCH C CH CH CH CH CH OMe OMe 943 1 CH CH CH CH C N CH CH CH CH OMe OMe944 1 CH CH CH CH C CH N CH CH CH OMe OMe 945 1 CH CH CH CH C N CH CH CHN OMe OMe 946 1 CH CH CH CH C N N CH CH CH OMe OMe 947 1 CH CH CH CH CCH N CH N CH OMe absent 948 1 CH CH CH CH C CH CH N CH N absent OMe 9491 CH CH CH CH C CH CH N CH CH absent OMe 950 1 N CH CH CH C CH CH CH CHCH OMe OMe 951 1 N CH CH CH C N CH CH CH CH OMe OMe 952 1 N CH CH CH CCH N CH CH CH OMe OMe 953 1 N CH CH CH C N CH CH CH N OMe OMe 954 1 N CHCH CH C CH CH N CH N absent OMe 955 1 N CH CH CH C N CH CH CH CH OMe OMe956 1 N N CH CH C CH CH N CH N absent OMe 957 1 N N CH CH C CH CH CH CHCH OMe OMe 958 1 CH N CH CH C CH CH CH CH CH OMe OMe 959 1 CH N CH CH CN CH CH CH CH OMe OMe 960 1 CH N CH CH C CH N CH CH CH OMe OMe 961 1 CHN CH CH C CH N CH N CH OMe absent 962 1 CH N CH CH C N CH CH N CH OMeOMe 963 1 CH N CH CH C CH CH N CH N absent OMe 964 1 CH N CH CH C CH CHN CH CH absent OMe 965 1 N CH N CH C CH CH CH CH CH OMe OMe 966 1 N CH NCH C N CH CH CH CH OMe OMe 967 1 N CH N CH C CH N CH CH CH OMe OMe 968 1CH N CH N C CH CH CH CH CH OMe OMe 969 1 CH CH N N C CH CH CH CH CH OMeOMe 970 1 CH CH CH N C CH CH CH CH CH OMe OMe 971 1 CH CH CH N C CH CH NCH CH absent OMe

In a further embodiment, the present invention provides compounds offormula (Va) and (Vb), wherein o, Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈, Y₉,Y₁₀, R₅, and R₆ are as defined in examples 1297 to 1300:

In both, formulae (Va) and (Vb), o is 0.

Comp p Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆ 1297 0 CH CH CH CH C CH CHCH CH CH OMe H 1298 0 CH CH CH N C CH CH CH CH CH OMe H 1299 0 CH CH CHCH C CH CH CH CH CH O- H Phenyl 1300 0 CH CH N CH C CH CH CH CH CH OMeOMe

In a further embodiment, the present invention provides compounds offormula (VI), wherein X₁, n, Z, R₅, and R₆ are as defined in examples972 to 977:

(VI)

Comp X₁ Z n R₅ R₆ 972 CH₂ CH 1 F H 973 CH₂ N 1 F H 974 S N 1 F H 975 CH₂CH 1 OMe OMe 976 CH₂ N 1 OMe OMe 977 S N 1 OMe OMe

In a further embodiment, the present invention provides compounds offormula (VII), wherein X₁, n, Z, R₂, R₅, and R₆ are as defined inexamples 978 to 54:

(VII)

Comp X₁ Z n R₂ R₅ R₆ 978 CH₂ CH 1 Me F H 979 CH₂ N 1 Me F H 980 S N 1 MeF H 981 CH₂ CH 1 Me OMe OMe 982 CH₂ N 1 Me OMe OMe 983 S N 1 Me OMe OMe984 CH₂ CH 1 Cyclopropyl F H 985 CH₂ N 1 Cyclopropyl F H 986 S N 1Cyclopropyl F H 987 CH₂ CH 1 Cyclopropyl OMe OMe 988 CH₂ N 1 CyclopropylOMe OMe 989 S N 1 Cyclopropyl OMe OMe

In a further embodiment, the present invention provides compounds offormula (VIII), wherein X₁, n, R₅, and R₆ are as defined in examples 990to 993:

(VIII)

Comp X₁ n R5 R6 990 CH₂ 1 F H 991 S 1 F H 992 CH₂ 1 OMe OMe 993 S 1 OMeOMe

In a further embodiment, the present invention provides compounds offormula (IX), wherein X₁, n, R₂, R₅, and R₆ are as defined in examples994 to 1001:

(IX)

Comp X₁ n R₂ R₅ R₆ 994 CH₂ 1 Me F H 995 S 1 Me F H 996 CH₂ 1 Me OMe OMe997 S 1 Me OMe OMe 998 CH₂ 1 Cyclopropyl F H 999 S 1 Cyclopropyl F H1000 CH₂ 1 Cyclopropyl OMe OMe 1001 S 1 Cyclopropyl OMe OMe

In a further embodiment, the present invention provides compounds offormula (X), wherein o, R₅, and R₆ are as defined in examples 1002 to1005:

(X)

o is 0. Comp p R₅ R₆ 1002 0 F H 1003 0 OMe OMe 1004 1 F H 1005 1 OMe OMe

In a further embodiment, the present invention provides compounds offormula (XI), wherein o, R₂, R₅, and R₆ are as defined in examples 1006to 1013:

(XI)

Comp p R₂ R₅ R₆ 1006 0 Me F H 1007 0 Me OMe OMe 1008 0 Cyclopropyl F H1009 0 Cyclopropyl OMe OMe 1010 1 Me F H 1011 1 Me OMe OMe 1012 1Cyclopropyl F H 1013 1 Cyclopropyl OMe OMe

In a further embodiment, the present invention provides compounds offormula (XIIa) and (XIIb), wherein Z, Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈,Y₉, Y₁₀, R₅, and R₆ are as defined in examples 1014 to 1189:

(XIIa)

(XIIb)

Comp Z Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆ 1014 CH CH CH CH CH C CH CHCH CH CH H H 1015 N CH CH CH CH C CH CH CH CH CH H H 1016 CH CH CH CH CHC N CH CH CH CH H H 1017 N CH CH CH CH C N CH CH CH CH H H 1018 CH CH CHCH CH C CH N CH CH CH H H 1019 N CH CH CH CH C CH N CH CH CH H H 1020 CHCH CH CH CH C N CH CH CH N H H 1021 N CH CH CH CH C N CH CH CH N H H1022 CH CH CH CH CH C N N CH CH CH H H 1023 N CH CH CH CH C N N CH CH CHH H 1024 CH CH CH CH CH C CH N CH N CH H absent 1025 N CH CH CH CH C CHN CH N CH H 1026 CH CH CH CH CH C CH CH N CH N absent H 1027 N CH CH CHCH C CH CH N CH N H 1028 CH CH CH CH CH C CH CH N CH CH absent H 1029 NCH CH CH CH C CH CH N CH CH H 1030 CH N CH CH CH C CH CH CH CH CH H H1031 N N CH CH CH C CH CH CH CH CH H H 1032 CH N CH CH CH C N CH CH CHCH H H 1033 N N CH CH CH C N CH CH CH CH H H 1034 CH N CH CH CH C CH NCH CH CH H H 1035 N N CH CH CH C CH N CH CH CH H H 1036 CH N CH CH CH CN CH CH CH N H H 1037 N N CH CH CH C N CH CH CH N H H 1038 CH N CH CH CHC CH CH N CH N absent H 1039 N N CH CH CH C CH CH N CH N H 1040 CH N CHCH CH C N CH CH CH CH H H 1041 N N CH CH CH C N CH CH CH CH H H 1042 CHN N CH CH C CH CH N CH N absent H 1043 N N N CH CH C CH CH N CH N H 1044CH N N CH CH C CH CH CH CH CH H H 1045 N N N CH CH C CH CH CH CH CH H H1046 CH CH N CH CH C CH CH CH CH CH H H 1047 N CH N CH CH C CH CH CH CHCH H H 1048 CH CH N CH CH C N CH CH CH CH H H 1049 N CH N CH CH C N CHCH CH CH H H 1050 CH CH N CH CH C CH N CH CH CH H H 1051 N CH N CH CH CCH N CH CH CH H H 1052 CH CH N CH CH C CH N CH N CH H absent 1053 N CH NCH CH C CH N CH N CH H 1054 CH CH N CH CH C N CH CH N CH H H 1055 N CH NCH CH C N CH CH N CH H H 1056 CH CH N CH CH C CH CH N CH N absent H 1057N CH N CH CH C CH CH N CH N H 1058 CH CH N CH CH C CH CH N CH CH absentH 1059 N CH N CH CH C CH CH N CH CH H 1060 CH N CH N CH C CH CH CH CH CHH H 1061 N N CH N CH C CH CH CH CH CH H H 1062 CH N CH N CH C N CH CH CHCH H H 1063 N N CH N CH C N CH CH CH CH H H 1064 CH N CH N CH C CH N CHCH CH H H 1065 N N CH N CH C CH N CH CH CH H H 1066 CH CH N CH N C CH CHCH CH CH H H 1067 N CH N CH N C CH CH CH CH CH H H 1068 CH CH CH N N CCH CH CH CH CH H H 1069 N CH CH N N C CH CH CH CH CH H H 1070 CH CH CHCH N C CH CH CH CH CH H H 1071 N CH CH CH N C CH CH CH CH CH H H 1072 CHCH CH CH N C CH CH N CH CH absent H 1073 N CH CH CH N C CH CH N CH CH H1074 CH CH CH CH CH C CH CH CH CH CH F H 1075 N CH CH CH CH C CH CH CHCH CH F H 1076 CH CH CH CH CH C N CH CH CH CH F H 1077 N CH CH CH CH C NCH CH CH CH F H 1078 CH CH CH CH CH C CH N CH CH CH F 1079 N CH CH CH CHC CH N CH CH CH F H 1080 CH CH CH CH CH C N CH CH CH N F H 1081 N CH CHCH CH C N CH CH CH N F H 1082 CH CH CH CH CH C N N CH CH CH F H 1083 NCH CH CH CH C N N CH CH CH F H 1084 CH CH CH CH CH C CH N CH N CH Fabsent 1085 N CH CH CH CH C CH N CH N CH F 1086 CH CH CH CH CH C CH CH NCH N absent 1087 N CH CH CH CH C CH CH N CH N 1088 CH CH CH CH CH C CHCH N CH CH absent H 1089 N CH CH CH CH C CH CH N CH CH H 1090 CH N CH CHCH C CH CH CH CH CH F H 1091 N N CH CH CH C CH CH CH CH CH F H 1092 CH NCH CH CH C N CH CH CH CH F H 1093 N N CH CH CH C N CH CH CH CH F H 1094CH N CH CH CH C CH N CH CH CH F H 1095 N N CH CH CH C CH N CH CH CH F H1096 CH N CH CH CH C N CH CH CH N F H 1097 N N CH CH CH C N CH CH CH N FH 1098 CH N CH CH CH C CH CH N CH N absent H 1099 N N CH CH CH C CH CH NCH N H 1100 CH N N CH CH C CH CH CH CH CH F H 1101 N N N CH CH C CH CHCH CH CH F H 1102 CH N N CH CH C CH CH N CH N absent H 1103 N N N CH CHC CH CH N CH N H 1104 CH CH N CH CH C CH CH CH CH CH F H 1105 N CH N CHCH C CH CH CH CH CH F H 1106 CH CH N CH CH C N CH CH CH CH F H 1107 N CHN CH CH C N CH CH CH CH F H 1108 CH CH N CH CH C CH N CH CH CH F H 1109N CH N CH CH C CH N CH CH CH F H 1110 CH CH N CH CH C CH N CH N CH Fabsent 1111 N CH N CH CH C CH N CH N CH F 1112 CH CH N CH CH C N CH CH NCH F absent 1113 N CH N CH CH C N CH CH N CH F 1114 CH CH N CH CH C CHCH N CH N absent H 1115 N CH N CH CH C CH CH N CH N H 1116 CH N CH N CHC CH CH CH CH CH F H 1117 N N CH N CH C CH CH CH CH CH F H 1118 CH N CHN CH C N CH CH CH CH F H 1119 N N CH N CH C N CH CH CH CH F H 1120 CH NCH N CH C CH N CH CH CH F H 1121 N N CH N CH C CH N CH CH CH F H 1122 CHCH N CH N C CH CH CH CH CH F H 1123 N CH N CH N C CH CH CH CH CH F H1124 CH CH CH N N C CH CH CH CH CH F H 1125 N CH CH N N C CH CH CH CH CHF H 1126 CH CH CH CH N C CH CH CH CH CH F H 1127 N CH CH CH N C CH CH CHCH CH F H 1128 CH CH CH CH N C CH N CH CH CH F H 1129 N CH CH CH N C CHN CH CH CH F H 1130 CH CH CH CH CH C CH CH CH CH CH OMe OMe 1131 N CH CHCH CH C CH CH CH CH CH OMe OMe 1132 CH CH CH CH CH C N CH CH CH CH OMeOMe 1133 N CH CH CH CH C N CH CH CH CH OMe OMe 1134 CH CH CH CH CH C CHN CH CH CH OMe OMe 1135 N CH CH CH CH C CH N CH CH CH OMe OMe 1136 CH CHCH CH CH C N CH CH CH N OMe OMe 1137 N CH CH CH CH C N CH CH CH N OMeOMe 1138 CH CH CH CH CH C N N CH CH CH OMe OMe 1139 N CH CH CH CH C N NCH CH CH OMe OMe 1140 CH CH CH CH CH C CH N CH N CH OMe absent 1141 N CHCH CH CH C CH N CH N CH OMe 1142 CH CH CH CH CH C CH CH N CH N absentOMe 1143 N CH CH CH CH C CH CH N CH N OMe 1144 CH CH CH CH CH C CH CH NCH CH absent OMe 1145 N CH CH CH CH C CH CH N CH CH OMe 1146 CH N CH CHCH C CH CH CH CH CH OMe OMe 1147 N N CH CH CH C CH CH CH CH CH OMe OMe1148 CH N CH CH CH C N CH CH CH CH OMe OMe 1149 N N CH CH CH C N CH CHCH CH OMe OMe 1150 CH N CH CH CH C CH N CH CH CH OMe OMe 1151 N N CH CHCH C CH N CH CH CH OMe OMe 1152 CH N CH CH CH C N CH CH CH N OMe OMe1153 N N CH CH CH C N CH CH CH N OMe OMe 1154 CH N CH CH CH C CH CH N CHN absent OMe 1155 N N CH CH CH C CH CH N CH N OMe 1156 CH N CH CH CH C NCH CH CH CH OMe OMe 1157 N N CH CH CH C N CH CH CH CH OMe OMe 1158 CH NN CH CH C CH CH N CH N absent OMe 1159 N N N CH CH C CH CH N CH N OMe1160 CH N N CH CH C CH CH CH CH CH OMe OMe 1161 N N N CH CH C CH CH CHCH CH OMe OMe 1162 CH CH N CH CH C CH CH CH CH CH OMe OMe 1163 N CH N CHCH C CH CH CH CH CH OMe OMe 1164 CH CH N CH CH C N CH CH CH CH OMe OMe1165 N CH N CH CH C N CH CH CH CH OMe OMe 1166 CH CH N CH CH C CH N CHCH CH OMe OMe 1167 N CH N CH CH C CH N CH CH CH OMe OMe 1168 CH CH N CHCH C CH N CH N CH OMe absent 1169 N CH N CH CH C CH N CH N CH OMe 1170CH CH N CH CH C N CH CH N CH OMe OMe 1171 N CH N CH CH C N CH CH N CHOMe OMe 1172 CH CH N CH CH C CH CH N CH N absent OMe 1173 N CH N CH CH CCH CH N CH N OMe 1174 CH CH N CH CH C CH CH N CH CH absent OMe 1175 N CHN CH CH C CH CH N CH CH OMe 1176 CH N CH N CH C CH CH CH CH CH OMe OMe1177 N N CH N CH C CH CH CH CH CH OMe OMe 1178 CH N CH N CH C N CH CH CHCH OMe OMe 1179 N N CH N CH C N CH CH CH CH OMe OMe 1180 CH N CH N CH CCH N CH CH CH OMe OMe 1181 N N CH N CH C CH N CH CH CH OMe OMe 1182 CHCH N CH N C CH CH CH CH CH OMe OMe 1183 N CH N CH N C CH CH CH CH CH OMeOMe 1184 CH CH CH N N C CH CH CH CH CH OMe OMe 1185 N CH CH N N C CH CHCH CH CH OMe OMe 1186 CH CH CH CH N C CH CH CH CH CH OMe OMe 1187 N CHCH CH N C CH CH CH CH CH OMe OMe 1188 CH CH CH CH N C CH CH N CH CHabsent OMe 1189 N CH CH CH N C CH CH N CH CH OMe

In a further embodiment, the present invention provides compounds offormula (XIII), wherein Z, R₅, and R₆ are as defined in examples 1190 to1193:

(XIII)

Comp Z R₅ R₆ 1190 CH F H 1191 N F H 1192 CH OMe OMe 1193 N OMe OMe

In a further embodiment, the present invention provides compounds offormula (XIV), wherein R₅, and R₅ are as defined in examples 1194 to1195:

(XIV)

Comp R₅ R₆ 1194 F H 1195 OMe OMe

In a further embodiment, the present invention provides compounds offormula (XVa) and (XVb), wherein Y Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈, Y₉,Y₁₀, R₅, and R₅ are as defined in examples 1196 to 1282:

(XVa)

(XVb)

Comp Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆ 1196 CH CH CH CH C CH CH CH CHCH H H 1197 CH CH CH CH C N CH CH CH CH H H 1198 CH CH CH CH C CH N CHCH CH H H 1199 CH CH CH CH C N CH CH CH N H H 1200 CH CH CH CH C N N CHCH CH H H 1201 CH CH CH CH C CH N CH N CH H ab- sent 1202 CH CH CH CH CCH CH N CH N ab- H sent 1203 CH CH CH CH C CH CH N CH CH ab- H sent 1204N CH CH CH C CH CH CH CH CH H H 1205 N CH CH CH C N CH CH CH CH H H 1206N CH CH CH C CH N CH CH CH H H 1207 N CH CH CH C N CH CH CH N H H 1208 NCH CH CH C CH CH N CH N ab- H sent 1209 N CH CH CH C N CH CH CH CH H H1210 N N CH CH C CH CH N CH N ab- H sent 1211 N N CH CH C CH CH CH CH CHH H 1212 CH N CH CH C CH CH CH CH CH H H 1213 CH N CH CH C N CH CH CH CHH H 1214 CH N CH CH C CH N CH CH CH H H 1215 CH N CH CH C CH N CH N CH Hab- sent 1216 CH N CH CH C N CH CH N CH H H 1217 CH N CH CH C CH CH N CHN ab- H sent 1218 CH N CH CH C CH CH N CH CH ab- H sent 1219 N CH N CH CCH CH CH CH CH H H 1220 N CH N CH C N CH CH CH CH H H 1221 N CH N CH CCH N CH CH CH H H 1222 CH N CH N C CH CH CH CH CH H H 1223 CH CH N N CCH CH CH CH CH H H 1224 CH CH CH N C CH CH CH CH CH H H 1225 CH CH CH NC CH CH N CH CH ab- H sent 1226 CH CH CH CH C CH CH CH CH CH F H 1227 CHCH CH CH C N CH CH CH CH F H 1228 CH CH CH CH C CH N CH CH CH F H 1229CH CH CH CH C N CH CH CH N F H 1230 CH CH CH CH C N N CH CH CH F H 1231CH CH CH CH C CH N CH N CH F ab- sent 1232 CH CH CH CH C CH CH N CH Nab- sent 1233 CH CH CH CH C CH CH N CH CH ab- H sent 1234 N CH CH CH CCH CH CH CH CH F H 1235 N CH CH CH C N CH CH CH CH F H 1236 N CH CH CH CCH N CH CH CH F H 1237 N CH CH CH C N CH CH CH N F H 1238 N CH CH CH CCH CH N CH N ab- H sent 1239 N N CH CH C CH CH CH CH CH F H 1240 N N CHCH C CH CH N CH N ab- H sent 1241 CH N CH CH C CH CH CH CH CH F H 1242CH N CH CH C N CH CH CH CH F H 1243 CH N CH CH C CH N CH CH CH F H 1244CH N CH CH C CH N CH N CH F ab- sent 1245 CH N CH CH C N CH CH N CH Fab- sent 1246 CH N CH CH C CH CH N CH N ab- H sent 1247 N CH N CH C CHCH CH CH CH F H 1248 N CH N CH C N CH CH CH CH F H 1249 N CH N CH C CH NCH CH CH F H 1250 CH N CH N C CH CH CH CH CH F H 1251 CH CH N N C CH CHCH CH CH F H 1252 CH CH CH N C CH CH CH CH CH F H 1253 CH CH CH N C CH NCH CH CH F H 1254 CH CH CH CH C CH CH CH CH CH OMe OMe 1255 CH CH CH CHC N CH CH CH CH OMe OMe 1256 CH CH CH CH C CH N CH CH CH OMe OMe 1257 CHCH CH CH C N CH CH CH N OMe OMe 1258 CH CH CH CH C N N CH CH CH OMe OMe1259 CH CH CH CH C CH N CH N CH OMe ab- sent 1260 CH CH CH CH C CH CH NCH N ab- OMe sent 1261 CH CH CH CH C CH CH N CH CH ab- OMe sent 1262 NCH CH CH C CH CH CH CH CH OMe OMe 1263 N CH CH CH C N CH CH CH CH OMeOMe 1264 N CH CH CH C CH N CH CH CH OMe OMe 1265 N CH CH CH C N CH CH CHN OMe OMe 1266 N CH CH CH C CH CH N CH N ab- OMe sent 1267 N CH CH CH CN CH CH CH CH OMe OMe 1268 N N CH CH C CH CH N CH N ab- OMe sent 1269 NN CH CH C CH CH CH CH CH OMe OMe 1270 CH N CH CH C CH CH CH CH CH OMeOMe 1271 CH N CH CH C N CH CH CH CH OMe OMe 1272 CH N CH CH C CH N CH CHCH OMe OMe 1273 CH N CH CH C CH N CH N CH OMe ab- sent 1274 CH N CH CH CN CH CH N CH OMe OMe 1275 CH N CH CH C CH CH N CH N ab- OMe sent 1276 CHN CH CH C CH CH N CH CH ab- OMe sent 1277 N CH N CH C CH CH CH CH CH OMeOMe 1278 N CH N CH C N CH CH CH CH OMe OMe 1279 N CH N CH C CH N CH CHCH OMe OMe 1280 CH N CH N C CH CH CH CH CH OMe OMe 1281 CH CH N N C CHCH CH CH CH OMe OMe 1282 CH CH CH N C CH CH CH CH CH OMe OMe

In a further embodiment, the present invention provides compounds offormula (XVa) and (XVb), wherein Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈, Y₉,Y₁₀, R₅, and R₆ are as defined in examples 1310 to 1319:

(XVa)

(XVb)

Comp Y₁ Y₂ Y₃ Y₄ Y₅ Y₆ Y₇ Y₈ Y₉ Y₁₀ R₅ R₆ 1301 CH CH CH CH C CH CH CH CHCH OMe H 1302 CH CH CH N C CH CH CH CH CH OMe H 1303 N CH CH CH C CH CHCH CH CH OMe H 1304 CH CH N CH C CH CH CH CH CH OMe H 1305 CH N CH CH CCH CH CH CH CH OMe H 1306 N CH N CH C CH CH CH CH CH OMe H 1307 N CH CHN C CH CH CH CH CH OMe H 1308 CH CH N CH C CH CH CH CH CH OMe OMe 1309 NCH CH N C CH CH CH CH CH OMe OMe 1310 N CH CH N C CH CH CH CH CH F H1311 CH CH CH CH C CH CH CH CH CH O- H phe- nyl 1312 CH CH CH CH C CH CHCH CH CH O- H cy- clo- hex- yl 1313 CH CH CH CH C CH CH CH CH CH pro- Hpyl- oxy 1314 CH CH CH CH C CH CH CH CH CH pro- H pan- 2- yl- oxy 1315CH CH CH CH C CH CH CH CH CH OMe H subst. with Me 1316 CH CH CH CH C CHCH CH CH CH OMe OMe subst. with Me 1317 CH CH CH CH C CH CH CH CH CH ClOMe subst. with F 1318 CH CH CH CH C CH CH CH CH CH OMe OMe subst. withF 1319 CH CH CH CH C CH CH CH CH CH F H subst. with F

In a further embodiment, the present invention provides compounds offormula (XVI), wherein R₅, and R₆ are as defined in examples 1283 to1284:

(XVI)

Comp R5 R6 1283 F H 1284 OMe OMe

In a further embodiment, the present invention provides compounds offormula (XVII), wherein R₂, R₅, and R₆ are as defined in examples 1285to 1288:

(XVII)

Comp R2 R5 R6 1285 Me F H 1286 Me OMe OMe 1287 Cyclopropy F H 1288Cyclopropy OMe OMe

In a further embodiment, the present invention provides compounds offormula (XVIII), wherein X₁, n, R₅, and R₆ are as defined in examples1320 to 1323:

(XVIII)

Comp X₁ n R5 R6 1320 CH₂ 1 F H 1321 S 1 F H 1322 CH₂ 1 OMe OMe 1323 S 1OMe OMe

In a preferred embodiment, the present invention provides compounds offormula (I), or a pharmaceutically acceptable salt, solvate or polymorphthereof, including all tautomers and stereoisomers thereof, wherein saidcompound of formula (I) is selected from:

Syn- Exam- the- hQC hQC ple sis K_(i) K_(i) Com- Exam- Mol [μM] [μM]pound ple Compound Name Structure Formula Weight pH6 pH8 93 A25-[3-({4′-fluoro- [1,1′-biphenyl]- 2-yl}amino) propyl]-1,3,4-thiadiazol-2-amine

C₁₇H₁₇FN₄S 328.40 2.6 1102 94 A3 5-{[2-({4′-fluoro- [1,1′-biphenyl]-2-yl}amino)ethyl] sulfanyl}-1,3,4- thiadiazol-2-amine

C₁₆H₁₅FN₄S₂ 346.44 2.97 11.51 178 A4 5-{[2-({3′,4′- dimethoxy-[1,1′-biphenyl]-2-yl} amino)ethyl] sulfanyl}-1,3,4- thiadiazol-2-amine

C₁₈H₂₀N₄O₂S₂ 388.50 1.10 0.97 328 B1 4′-fluoro-N-[3-(4- methyl-4H-1,2,4-triazol-3-yl) propyl]-[1,1′- biphenyl]-2- amine

C₁₈H₁₉FN₄ 310.36 1.97 2.86 384 B3 3′,4′-dimethoxy-N- [3-(4-methyl-4H-1,2,4-triazol-3-yl) propyl]-[1,1′- biphenyl]-2-amine

C₂₀H₂₄N₄O₂ 352.43 0.13 0.26 505 C2 5-[4-({4′-fluoro- [1,1′-biphenyl]-2-yl}amino) phenyl]-1,3,4- thiadiazol-2-amine

C₂₀H₁₅FN₄S 362.42 1.52 1.81 561 C3 5-(4-{[2-(3,4- dimethoxyphenyl)phenyl]amino} phenyl)-1,3,4- thiadiazol-2-amine

C₂₂H₂₀N₄O₂S 404.48 0.42 1.09 1289 C4 5-(4-{[2-(4- methoxyphenyl)phenyl]amino} phenyl)-1,3,4- thiadiazol-2-amine

C₂₁H₁₈N₄OS 374.46 1.87 1.48 1290 C5 N-[4-(5-amino- 1,3,4-thiadiazol-2-yl)phenyl]-3-(4- methoxyphenyl) pyridin-2-amine

C₂₀H₁₇N₅O_(S) 375.44 4.17 4.70 1291 C6 N-[4-(5-amino- 1,3,4-thiadiazol-2-yl)phenyl]-3- (4-methoxy- phenyl)pyridin- 4-amine

C₂₀H₁₇N₅OS 375.44 7.16 4.22 1292 C7 N-[4-(5-amino- 1,3,4-thiadiazol-2-yl)phenyl]-3- (3,4-dimethoxy- phenyl)pyridin- 4-amine

C₂₁H₁₉N₅O₂S 405.47 54.69 7.46 521 C8 N-[4-(5-amino- 1,3,4-thiadiazol-2-yl)phenyl]-3- (4-fluorophenyl) pyridin-2-amine

C₁₉H₁₄FN₅S 363.41 2.69 4.27 1293 C9 N-[4-(5-amino- 1,3,4-thiadiazol-2-yl)phenyl]-3- (4-fluorophenyl) pyrazin-2-amine

C₁₈H₁₃FN₆S 364.39 1.66 6.89 1294 C10 5-(4-{[2-(4- phenoxyphenyl)phenyl]amino} phenyl)-1,3,4- thiadiazol-2-amine

C₂₆H₂₀N₄OS 436.52 4.37 2.23 1295 C11 5-(4-{[2-(4- propoxyphenyl)phenyl]amino} phenyl)-1,3,4- thiadiazol-2-amine

C₂₃H₂₂N₄OS 402.51 2.15 2.36 1296 C12 5-[4-({2-[4- (propan-2-yloxy)phenyl] phenyl}amino) phenyl]-1,3,4- thiadiazol-2-amine

C₂₃H₂₂N₄OS 402.51 1.51 3.27 826 D1 4′-fluoro-N-[4- (4-methyl-4H-1,2,4-triazol-3-yl) phenyl]-[1,1′- biphenyl]-2-amine

C₂₁H₁₇FN₄ 344.38 1.44 1.74 854 D2 3′,4′-dimethoxy- N-[4-(4-methyl-4H-1,2,4-triazol- 3-yl)phenyl]- [1,1′-biphenyl]- 2-amine

C₂₃H₂₂N₄O₂ 386.45 0.44 1.48 1297 D3 N-[2-(4- methoxyphenyl)phenyl]-4-(4- methyl-4H- 1,2,4-triazol-3- yl)aniline

C₂₂H₂₀N₄O 356.42 0.99 1.69 1298 D4 2-(4-methoxy- phenyl)-N-[4-(4-methyl-4H- 1,2,4-triazol-3- yl)phenyl] pyridin-3-amine

C₂₁H₁₉N₅O 357.40 1.70 3.37 852 D5 2-(4-fluoro- phenyl)-N-[4-(4-methyl-4H- 1,2,4-triazol- 3-yl)phenyl] pyridin-3-amine

C₂₀H₁₆FN₅ 345.37 2.69 5.05 1299 D6 4-(4-methyl-4H- 1,2,4-triazol-3-yl)-N-[2-(4- phenoxyphenyl) phenyl]aniline

C₂₇H₂₂N₄O 418.48 1.33 1.81 1300 D7 3-(3,4- dimethoxy- phenyl)-N-[4-(4-methyl- 4H-1,2,4- triazol-3-yl) phenyl] pyridin-4-amine

C₂₂H₂₁N₅O₂ 387.43 Not deter- mined 10.07 973 E2 N-[3-(5-amino-1,3,4-thia- diazol-2-yl) propyl]-4- fluorobenzene- 1-sulfonamide

C₁₁H₁₃FN₄O₂S₂ 316.37 18.08 9.38 974 E3 N-{2-[(5-amino- 1,3,4-thia-diazol-2-yl) sulfanyl]ethyl}- 4-fluoro- benzene-1- sulfonamide

C₁₀H₁₁FN₄O₂S₃ 334.41 19.91 26.48 979 F2 5-(3-{[(4- fluorophenyl)(methyl)oxo- λω-sulfanyl- idene]amino} propyl)-1,3,4- thiadiazol-2-amine

C₁₂H₁₅FN₄OS₂ 314.40 11.41 11.70 990 G1 4-fluoro-N-[3- (4-methyl-4H-1,2,4-triazol-3- yl)propyl] benzene-1- sulfonamide

C₁₂H₁₅FN₄O₂S 298.33 — — 991 G2 4-fluoro-N-{2- [(4-methyl-4H-1,2,4-triazol-3- yl)sulfanyl] ethyl}benzene- 1-sulfonamide

C₁₁H₁₃FN₄O₂S₂ 316.37 8.84 11.49 1332 G5 [(3,4- dimethoxy- phenyl)sulfamoyl] ({2-[(4- methyl-4H-

C₁₃H₁₉N₅O₄S₂ 373.45 13.63 11.76 1,2,4-triazol- 3-yl)sulfanyl]ethyl})amine 1002 I1 N-[4-(2-amino- 1,3-thiazol-5- yl)phenyl]-4-fluorobenzene- 1-sulfonamide

C₁₅H₁₂FN₃O₂S₂ 349.40 2.93 2.64 1003 I2 N-[4-(2-amino- 1,3-thiazol-5-yl)phenyl]-3,4- dimethoxy- benzene-1- sulfonamide

C₁₇H₁₇N₃O₄S₂ 391.46 0.20 0.34 1075 L2 5-(1-{4′- fluoro-[1,1′-biphenyl]-2- yl}piperidin- 4-yl)-1,3,4- thiadiazol-2- amine

C₁₉H₁₉FN₄S 354.44 0.09 0.248 1190 M1 5-[1-(4- fluorobenzene- sulfonyl)piperidin-4- yl]-1,3-thiazol- 2-amine

C₁₄H₁₆FN₃O₂S₂ 341.42 1.32 1.70 1191 M2 5-[1-(4-fluoro- benzenesulfonyl)piperidin-4-yl]- 1,3,4-thiadiazol- 2-amine

C₁₃H₁₅FN₄O₂S₂ 342.41 1.18 1.60 1194 N1 1-(4-fluoro- benzenesulfonyl)-4-(4-methyl-4H- 1,2,4-triazol-3- yl)piperidine

C₁₄H₁₇FN₄O₂S 324.37 3.05 3.30 1226 O1 N-[(1H-1,3- benzodiazol-5-yl)methyl]-4′- fluoro-[1,1′- biphenyl]-2- amine

C₂₀H₁₆FN₃ 317.35 5.91 5.29 1254 O2 N-[(1H-1,3- benzodiazol-5-yl)methyl]-3′,4′- dimethoxy-[1,1′- biphenyl]-2-amine

C₂₂H₂₁N₃O₂ 359.42 0.12 0.27 1301 O3 N-(1H-1,3- benzodiazol-5-ylmethyl)-2-(4- methoxyphenyl) aniline

C₂₁H₁₉N₃O 329.39 1.44 1.65 1302 O4 N-(1H-1,3- benzodiazol-5-ylmethyl)-2-(4- methoxyphenyl) pyridin-3-amine

C₂₀H₁₈N₄O 330.38 9.52 2.96 1303 O5 N-(1H-1,3- benzodiazol-5-ylmethyl)-3-(4- methoxyphenyl) pyridin-2-amine

C₂₀H₁₈N₄O 330.38 2.74 2.41 1304 O6 N-(1H-1,3- benzodiazol-5-ylmethyl)-3-(4- methoxyphenyl) pyridin-4-amine

C₂₀H₁₈N₄O 330.38 15.05 10.85 1305 O7 N-(1H-1,3- benzodiazol-5-ylmethyl)-4-(4- methoxyphenyl) pyridin-3-amine

C₂₀H₁₈N₄O 330.38 11.14 4.24 1306 O8 N-(1H-1,3- benzodiazol-5-ylmethyl)-5-(4- methoxyphenyl) pyrimidin-4- amine

C₁₉H₁₇N₅O 331.37 Not deter- mined 18.31 1307 O9 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(4- methoxyphenyl) pyrazin-2-amine

C₁₉H₁₇N₅O 331.37 1.90 2.21 1308 O10 N-(1H-1,3- benzodiazol-5-ylmethyl)-3- (3,4-dimethoxy- phenyl)pyridin- 4-amine

C₂₁H₂₀N₄O₂ 360.40 1.63 0.88 1262 O11 N-(1H-1,3- benzodiazol-5-ylmethyl)-3- (3,4-dimethoxy- phenyl)pyridin- 2-amine

C₂₁H₂₀N₄O₂ 360.40 0.10 0.23 1309 O12 N-(1H-1,3- benzodiazol-5-ylmethyl)-3- (3,4-dimethoxy- phenyl)pyrazin- 2-amine

C₂₀H₁₉N₅O₂ 361.39 0.13 0.42 1252 O13 N-(1H-1,3- benzodiazol-5-ylmethyl)-2- (4-fluoro- phenyl)pyridin- 3-amine

C₁₉H₁₅FN₄ 318.34 145.42 21.96 1234 O14 N-(1H-1,3- benzodiazol-5-ylmethyl)-3- (4-fluorophenyl) pyridin-2-amine

C₁₉H₁₅FN₄ 318.34 58.79 12.28 1310 O15 N-(1H-1,3- benzodiazol-5-ylmethyl)-3- (4-fluorophenyl) pyrazin-2-amine

C₁₈H₁₄FN₅ 319.33 10.52 11.74 1311 O16 N-(1H-1,3- benzodiazol-5-ylmethyl)-2-(4- phenoxyphenyl) aniline

C₂₆H₂₁N₃O 391.46 4.34 2.11 1312 O17 N-(1H-1,3- benzodiazol-5-ylmethyl)-2-[4- (cyclohexyloxy) phenyl]aniline

C₂₆H₂₇N₃O 397.51 2.03 4.17 1313 O18 N-(1H-1,3- benzodiazol-5-ylmethyl)-2-(4- propoxyphenyl) aniline

C₂₃H₂₃N₃O 357.44 3.59 2.64 1314 O19 N-(1H-1,3- benzodiazol-5-ylmethyl)-2-[4- (propan-2- yloxy)phenyl] aniline

C₂₃H₂₃N₃O 357.44 1.53 3.39 1315 O20 N-(1H-1,3- benzodiazol-5-ylmethyl)-2-(4- methoxyphenyl)- 3-methylaniline

C22H21N3O 343.42 2.38 1.64 1316 O21 N-(1H-1,3- benzodiazol-5-ylmethyl)-2- (3,4-dimethoxy- phenyl)-3- methylaniline

C23H23N3O2: 373.45 0.43 0.42 1317 O22 N-(1H-1,3- benzodiazol-5-ylmethyl)-2-(4- chlorophenyl)- 3-fluoroaniline

C20H15ClFN3 351.8 4.89 6.83 1318 O23 N-(1H-1,3- benzodiazol-5-ylmethyl)-2- (3,4-dimethoxy- phenyl)-3- fluoroaniline

C22H20FN3O2 377.41 0.055 0.10 1319 O24 N-(1H-1,3- benzodiazol-5-ylmethyl)-3- fluoro-2-(4- fluorophenyl) aniline

C20H15F2N3 335.35 5.81 9.41 1283 P1 N-[(1H-1,3- benzodiazol-5-yl)methyl]-4- fluorobenzene- 1-sulfonamide

C₁₄H₁₂FN₃O₂S 305.32 38.34 24.74 1285 Q1 [(1H-1,3- benzodiazol-5-yl)methyl][(4- fluorophenyl) (methyl)oxo- λω- sulfanylidene] amine

C₁₅H₁₄FN₃OS 303.35 8.05 5.18

Synthesis of the Examples Synthesis Method A

4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanenitrile4′-fluoro-[1,1′-biphenyl]-2-amine (0.5 g, 2.7 mmol), sodiumcyanoborohydride (0.25 g, 4.0 mmol) and 4-oxobutanenitrile (0.44 g, 5.3mmol) were dissolved in dry MeOH (15 mL) and acetic acid was added (0.5mL). Reaction was stirred over 2 h until full consumption of amine wasobserved via UPLC analysis. After this time reaction mixture was dilutedwith saturated sodium bicarbonate solution (40 mL) and extracted withethyl acetate (3×20 mL). Combined organic layers were dried over sodiumsulfate, filtered and evaporated and purified via column chromatographyusing ethyl acetate in hexanes 10-20% as eluent to give pure titlecompound (0.17 g, 12%).

5-[3-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine(A2) 4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanenitrile (0.16 g, 0.6mmol) and thiosemicarbazide (0.06 g, 0.7 mmol) were dissolved intrifluoroacetic acid (1.3 mL). Reaction was monitored via UPLC analysis.After completion of the reaction, solvent was removed in vacuo and crudematerial was purified via column chromatography using MeOH in DCM 0-2%as eluent to give pure title compound (70 mg, 33%). LCMS-Method 10 (200nm): RT=5.81 min, 95.2% purity, [M+1]=329.2, ¹H NMR (300 MHz, DMSO-d₆) δ7.46-7.36 (m, 2H), 7.32-7.23 (m, 2H), 7.20-7.11 (m, 1H), 7.05-6.89 (m,3H), 6.76-6.55 (m, 2H), 4.61 (t, J=5.9 Hz, 1H), 3.10 (q, J=6.6 Hz, 2H),2.82 (t, J=7.5 Hz, 2H), 1.85 (p, J=7.2 Hz, 2H).

Synthesis Method B

Step 1

2-substituted aniline (1.0 eq.), sodium cyanoborohydride (1.5 eq.) andt-butyldimethylsilyloxyacetaldehyde (2.0 eq.) were dissolved in dry MeOH(30.0 vol.) and acetic acid was added (1.0 vol.). Reaction was stirredover 1-2 h until full consumption of amine was observed via UPLCanalysis. After this time reaction mixture was diluted with saturatedsodium bicarbonate solution (40 mL) and extracted with ethyl acetate(3×20 mL). Combined organic layers were dried over sodium sulfate,filtered and evaporated, used in next step without further purification.

Step 2

Product from step 1 (1.0 eq.) and tetrabutylammonium fluoride trihydrate(1.05 eq.) were dissolved in THF (40.0 vol.). Reaction was monitored viaUPLC analysis. After completion the reaction, solvent was removed invacuo and crude material was taken to step 3.

5-{[2-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine(A3). To solution of 2-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)ethan-1-ol(0.58 g, 2.5 mmol), 2-amino-5-mercapto-thiadiazole (0.50 g, 3.8 mmol)and triphenylphosphine (1.18 g, 4.5 mmol) in anhydrous THF (16.0 mL)diethyleneazodicarboxylate (0.66 g, 3.8 mmol) was added dropwise.Reaction mixture was stirred overnight at room temperature. After thistime solvents were removed in vacuo. Crude product was purified viacolumn chromatography using 0-3% MeOH in DCM and additional repurifiedvia preparative TLC method using MeOH in DCM as eluent. Finalre-purification was performed via preparative HPLC method to give pureproduct (40 mg, 7%) LCMS-Method 7 (200 nm): RT=5.81 min, 98.7% purity,[M]=346.0, ¹H NMR (300 MHz, Methanol-d₄) δ 7.48-7.31 (m, 1H), 7.27-7.10(m, 2H), 7.01 (dd, J=7.4, 1.6 Hz, 1H), 6.84-6.52 (m, 1H), 3.47 (t, J=6.6Hz, 1H), 3.26 (t, J=6.6 Hz, 1H).

5-{[2-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine(A4). To solution of2-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)ethan-1-ol (0.9 g, 8.3mmol), 2-amino-5-mercapto-thiadiazole (1.0 g, 7.5 mmol) andtriphenylphosphine (2.17 g, 8.3 mmol) in anhydrous THF (10.0 mL)diethyleneazadicarboxylate (2.25 g, 9.8 mmol) was added dropwise in 5 mLof anhydrous tetrahydrofurane. Reaction mixture was stirred overnight atroom temperature. After this time solvents were removed in vacuo. Crudeproduct was purified via column chromatography using 0-3% MeOH in DCMand re-purified via preparative HPLC method to give pure product (80 mg,7%) LCMS-Method 7 (205 nm): RT=5.27 min, 98.1% purity, [M]=386.9, ¹H NMR(300 MHz, DMSO-d₆) δ 7.30 (s, 1H), 7.14 (td, J=7.8, 7.3, 1.7 Hz, 1H),7.09-6.96 (m, 2H), 6.89 (dd, J=8.2, 2.0 Hz, 0H), 6.75-6.61 (m, 1H), 4.94(t, J=6.0 Hz, 1H), 3.79 (d, J=1.8 Hz, 3H), 3.38 (d, J=6.5 Hz, 1H), 3.24(t, J=6.4 Hz, 1H).

Synthesis Method C

Step 1

To the solution of amine (4.27 mmol) in MeOH (25.0 mL) methyl4-oxobutanoate (0.99 g, 8.54 mmol) and acetic acid (0.8 mL) was added.The reaction mixture was stirred for 1.5 hours at ambient temperature.After that time NaBH₃CN (0.40 mg, 6.41 mmol) was added and the mixturewas stirred for 1 h. Reaction was quenched with saturated solution ofNaHCO₃. The water layer was extracted with DCM (3×20 mL). Combinedorganic layers were dried over sodium sulfate, filtered, evaporated toprovide the product.

methyl 4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanoate (0.875 g, 71%)4′-fluoro-[1,1′-biphenyl]-2-amine was used. Crude (1.47 g) was purifiedvia column chromatography using 100% DCM as eluent. UPLC (254 nm):RT=4.14 min, 76% purity, [M+H]=288.20.

methyl 4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)butanoate (1.00 g,71%) 3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine was used. Crude product waspurified via column chromatography using 0-20% EA in hexane as eluent.

Step 2

To the solution of corresponding starting material (3.04 mmol) in EtOH(30 mL) 50% hydrazine in H₂O (5.0 eq) was added. Reaction mixture wasstirred for 18 hour at 80° C. After that time the solvent was evaporatedto give pure compound.

4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanehydrazide (0.85 g, 96%).Methyl 4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanoate (0.875 g, 3.04mmol) as starting material was used. UPLC (254 nm): RT=3.06 min,[M+H]=288.35.

4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)butanehydrazide (0.97 g,97%). Methyl 4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)butanoate(1.0 g, 3.04 mmol) as starting material was used. UPLC (254 nm): RT=2.82min, [M+H]=330.30.

Step 3

To the solution of corresponding starting material (2.6 mmol) in MeOH (8mL) N,N-dimethylforamide dimethylacetal (311 mg, 2.6 mmol) was added.Reaction mixture was stirred for 1 hour at 80° C. After that timesolvent was evaporated to obtain desired product.

N′-[(1E)-(di methylami no)methylidene]-4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butane-hydrazide (0.894g, 100%). 4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanehydrazide (0.75g, 2.61 mmol) was used as starting material. UPLC (254 nm): RT=3.40 min,[M+H]=343.15.

4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)-N′-[(1E)-(dimethylamino)methylidene]-butanehydrazide(1.014 g, 100%).4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)butane-hydrazide (0.869g, 2.64 mmol) was used as starting material. UPLC (254 nm): RT=3.40 min,[M+H]=385.30.

Step 4

MeNH₂ 2M in THF (20 eq) was added to the solution of correspondingstarting material in anhydrous THF (10.0 mL) under argon atmosphere.Reaction mixture was cooled to 0° C. and acetic acid (2 mL) wascarefully added. Reaction mixture was stirred for 18 hours at 100° C.After that time reaction was cooled to room temperature and water (5 mL)was added. Layers were separated and water layer was extracted threetimes with EA (3×20 mL). Combined organic layers were dried over sodiumsulfate, filtered and evaporated. Crude product was purified via columnchromatography using 0-4% MeOH in DCM as eluent and then re-purified viapreparative HPLC. Fraction containing the title compound in pure formwas concentrated to give the product.

4′-fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1′-biphenyl]-2-amine(B1) (101 mg, 11%)N′-[(1E)-(dimethylamino)methylidene]-4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butane-hydrazide(1.00 g, 2.92 mmol) was used as starting material. LCMS-Method 2 (220nm): RT=4.78 min, 98.89% purity. ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (s,1H), 7.46-7.36 (m, 2H), 7.32-7.21 (m, 2H), 7.21-7.14 (m, 1H), 6.95 (d,J=1.7 Hz, 1H), 6.72-6.61 (m, 2H), 4.10 (q, J=5.3 Hz, 2H), 3.54 (s, 3H),2.69 (d, J=7.5 Hz, 2H), 1.95-1.84 (m, 2H).

3′,4′-dimethoxy-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1′-biphenyl]-2-amine(B3) (5 mg, 0.4%).4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)-N′-[(1E)-(dimethylamino)-methylidene]-butanehydrazide(1.10 g, 2.86 mmol) was used as starting material. LCMS-Method 8 (210nm): RT=12.12 min, 99.45% purity. ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (s,1H), 7.09-6.84 (m, 4H), 6.66 (d, J=7.9 Hz, 2H), 4.11 (q, J=5.4 Hz, 2H),3.79 (d, J=5.4 Hz, 3H), 3.53 (s, 3H), 3.40 (t, J=7.0 Hz, 2H), 3.18 (d,J=5.3 Hz, 3H), 1.89-1.96 (m, 2H).

Synthesis Method D

Step 1

N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine (0.5 g, 2.0 mmol),triethylamine (0.54 mL, 4.0 mmol), were dissolved in DCM (5 mL) andacetyl chloride (0.17 g, 2.15 mmol) was added dropwise at 5° C.,reaction was stirred at room temperature over 1 h, after this timeanother portion of triethylamine and acetyl chloride was added at 5° C.and reaction mixture was stirred over additional 30 min. The mixture wasdiluted with DCM (15.0 mL) and washed with sat. solution of sodiumbicarbonate (20 mL), water (20 mL). Title compound was obtained as 1:1mixture of acetylated (UPLC (254 nm): RT=3.13 min[M+H]=297.9) anddiacetylated amine (UPLC (254 nm): RT=3.58 min[M+H]=338.9). (0.40 g,60%). Used in next step without purification.

Step 2

N-{5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamideN-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (0.2 g, 0.67 mmol),4′-fluoro-[1,1′-biphenyl]-2-amine (0.12 g, 0.56 mmol), sodiumtert-butanolate (0.15 mg, 1.56 mmol) and XantPhos (40 mg, 0.07 mmol)were suspended in 1,4-dioxane (6 ml), Reaction mixture was degassed withargon flow over 20 min andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (35 mg, 0.035mmol) was added. Reaction was stirred overnight at 100° C. After thattime reaction mixture was cooled to room temperature, Filtered thrucelite, evaporated and purified via column chromatography using MeOH inDCM 0-3% as aluent to give pure product (0.24 g, 88%). UPLC (254 nm):RT=3.78 min, 85% purity, [M+H]=404.8.

5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine(C2) To solution ofN-{5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide(0.17 g, 0.42 mmol) in methanol (2.5 mL) concentrated hydrochloric acid(2.5 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (20 mL) and extracted with DCM (6×15 mL), organic layers werecombined, dried over sodium sulfate, filtered and evaporated. Crudeproduct was purified via preparative HPLC method to give pure product(40 mg, 25%) LCMS-Method 6 (200 nm): RT=20.57 min, 91.6% purity,[M+H]=363.14, LCMS (340 nm): RT=20.57 min, 99.2% purity, [M+H]=363.14,1H NMR (300 MHz, DMSO-d₆) δ 7.82 (s, 1H), 7.59-7.33 (m, 7H), 7.27-7.04(m, 5H), 6.89-6.54 (m, 2H).

N-{5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl}acetamideN-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34mmol), 2-(3,4-dimethoxyphenyl)aniline (60 mg, 0.28 mmol), sodiumtert-butanolate (75 mg, 1.56 mmol) and XantPhos (40 mg, 0.035 mmol) weresuspended in 1,4-dioxane (3 ml), Reaction mixture was degassed withargon flow over 20 min andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (17 mg, 0.017mmol) was added. Reaction was stirred overnight at 100° C. After thattime reaction mixture was cooled to room temperature, Filtered throughcelite, evaporated and purified via column chromatography using MeOH inDCM 0-3% as aluent to give pure product (0.2 g, 80%). UPLC (254 nm):RT=3.64 min, 85% purity, [M+H]=447.15.

5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine(C3). To solution ofN-{5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl}acetamide(0.20 g, 0.42 mmol) in methanol (3.0 mL) concentrated hydrochloric acid(3.0 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (20 mL) and extracted with DCM (6×15 mL), organic layers werecombined, dried over sodium sulfate, filtered and evaporated. Crudeproduct was purified via preparative HPLC method to give pure product(44 mg, 25%) LCMS (LCMS-Method 10, 200 nm), RT=5.22 min, 96.1% purity,[M+H]=405.11, 1H NMR (300 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.55-7.31 (m,6H), 7.37-7.13 (m, 5H), 6.81-6.64 (m, 2H), 3.53 (s, 3H), 3.50 (s, J=7.0Hz, 3H).

N-[5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (128 mg, 0.43mmol), 2-(4-methoxyphenyl)aniline (102 mg, 0.51 mmol), cesium carbonate(279 mg, 0.86 mmol) and XantPhos (50 mg, 0.09 mmol) were suspended in1,4-dioxane (3.8 mL). Reaction mixture was degassed with argon flow over20 min and tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.04 mmol)was added. Reaction was stirred at 100° C. for 96 hours. After that timereaction mixture was cooled to room temperature, Filtered thru celite,evaporated and purified via column chromatography using DCM/MeOH1:0→98:2 as a eluent to give product as a yellow solid (62.5 mg,35.01%). UPLC (254 nm): RT=7.14 min, 80.9% purity, [M+H]=417.10.

5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amineC4. To solution ofN-[5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide(63 mg, 0.15 mmol) in methanol (1.0 mL) concentrated hydrochloric acid(1.0 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (20 mL), methanol was evaporated and extraction with ethylacetate (2×10 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with Hex/EtOAc/MeOH 70:25:5 to give desiredproduct as a yellow solid (19.6 mg, 35%). LCMS (LCMS-Method 11, 200 nm):RT=2.75 min, 98.9% purity, [M+H]=375.21. ¹H NMR (300 MHz, DMSO-d₆) δ7.74 (s, 1H), 7.50-7.43 (m, 2H), 7.40-7.28 (m, 5H), 7.23-7.14 (m, 3H),6.98-6.91 (m, 2H), 6.84-6.78 (m, 2H), 3.75 (s, 3H).

N-[5-(4-{[3-(4-methoxyphenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (87 mg, 0.29 mmol),3-(4-methoxyphenyl)pyridin-2-amine (70 mg, 0.35 mmol), cesium carbonate(190 mg, 0.58 mmol) and XantPhos (34 mg, 0.06 mmol) were suspended in1,4-dioxane (2.6 mL). Reaction mixture was degassed with argon flow over20 min and tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.03 mmol)was added. Reaction was stirred at 100° C. for 72 hours. After that timereaction mixture was cooled to room temperature, Filtered thru celite,evaporated and purified via column chromatography using DCM/MeOH1:0→95:5 as a eluent to give product as a pale-yellow solid (114 mg,93.6%). UPLC (254 nm): RT=5.35 min, 65% purity, [M+H]=418.70.

N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine(C5). To solution ofN-[5-(4-{[3-(4-methoxyphenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide(114 mg, 0.27 mmol) in methanol (1.7 mL) concentrated hydrochloric acid(1.7 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (20 mL), methanol was evaporated and extraction with ethylacetate (2×15 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with DCM/MeOH 9:1 to give desired product as ayellowish solid (16.4 mg, 16%). LCMS-Method 5 (200 nm): RT=1.75 min,99.3% purity, [M+H]=376.19. ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (dd, J=4.9,1.9 Hz, 1H), 7.96 (s, 1H), 7.67-7.56 (m, 4H), 7.53 (dd, J=7.4, 1.9 Hz,1H), 7.47-7.40 (m, 2H), 7.25 (s, 2H), 7.10-7.04 (m, 2H), 6.98 (dd,J=7.4, 4.9 Hz, 1H), 3.82 (s, 3H).

N-[5-(4-{[3-(4-methoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34mmol), 3-(4-methoxyphenyl)pyridin-4-amine (81 mg, 0.40 mmol), cesiumcarbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) weresuspended in 1,4-dioxane (3 mL). Reaction mixture was degassed withargon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours.After that time reaction mixture was cooled to room temperature,Filtered thru celite, evaporated and purified via column chromatographyusing DCM/MeOH 1:0→95:5 as a eluent to give product as a yellow solid(75 mg, 53.6%). UPLC (310 nm): RT=3.96 min, 93% purity, [M+H]=418.95.

N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine(C6). To solution ofN-[5-(4-{[3-(4-methoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide(75 mg, 0.18 mmol) in methanol (1.12 mL) concentrated hydrochloric acid(1.12 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (20 mL), methanol was evaporated and extraction with ethylacetate (2×15 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with DCM/MeOH 9:1. Re-purification was performedvia preparative TLC eluted with DCM/MeOH 9:1 to give desired product asa whitish solid (32.0 mg, 47%). LCMS-Method 3 (200 nm): RT=3.01 min,99.8% purity, [M+H]=376.18. ¹H NMR (300 MHz, DMSO-d₆) δ 8.26-8.20 (m,2H), 8.00 (s, 1H), 7.66-7.61 (m, 2H), 7.45-7.40 (m, 2H), 7.32-7.18 (m,5H), 7.07-7.02 (m, 2H), 3.80 (s, 3H).

N-[5-(4-{[3-(3,4-dimethoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34mmol), 3-(3,4-dimethoxyphenyl)pyridin-4-amine (93 mg, 0.40 mmol), cesiumcarbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) weresuspended in 1,4-dioxane (3 mL). Reaction mixture was degassed withargon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours.After that time reaction mixture was cooled to room temperature,Filtered thru celite, evaporated and purified via column chromatographyusing DCM/MeOH 1:0→95:5 as a eluent to give product as a pale-yellowsolid (49 mg, 32.7%). UPLC (310 nm): RT=4.72 min, 100% purity,[M+H]=448.15.

N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine(C7). To solution ofN-[5-(4-{[3-(3,4-dimethoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide(49 mg, 0.11 mmol) in methanol (0.75 mL) concentrated hydrochloric acid(0.75 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (10 mL), methanol was evaporated and extraction with ethylacetate (2×10 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with DCM/MeOH 95:5 to give desired product as alight yellow solid (11 mg, 24.8%). LCMS-Method 3 (200 nm): RT=2.90 min,99.6% purity, [M+H]=406.17. ¹H NMR (300 MHz, DMSO-d₆) δ 8.28-8.22 (m,2H), 8.01 (s, 1H), 7.67-7.60 (m, 2H), 7.33-7.17 (m, 5H), 7.09-6.99 (m,3H), 3.77 (d, J=12.1 Hz, 6H).

N-[5-(4-{[3-(4-fluorophenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34mmol), 3-(4-fluorophenyl)pyridin-2-amine (52 mg, 0.28 mmol), cesiumcarbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) weresuspended in 1,4-dioxane (3 mL). Reaction mixture was degassed withargon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours.After that time reaction mixture was cooled to room temperature,Filtered thru celite, evaporated and purified via column chromatographyusing DCM/MeOH 1:0→99:1 as a eluent to give product as a yellowish solid(75 mg, 55.6%). UPLC (254 nm): RT=5.92 min, 96.8% purity, [M+H]=406.95.

N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine(C8). To solution ofN-[5-(4-{[3-(4-fluorophenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide(75 mg, 0.18 mmol) in methanol (1.2 mL) concentrated hydrochloric acid(1.2 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (20 mL), methanol was evaporated and extraction with ethylacetate (2×15 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with DCM/MeOH 95:5. Re-purification was performedvia preparative TLC eluted with DCM/MeOH 95:5 to give desired product asa yellowish solid (4.3 mg, 6.4%). LCMS-Method 2 (200 nm): RT=4.69 min,98.9% purity, [M+H]=364.18. ¹H NMR (300 MHz, Methanol-d₄) δ 8.22 (dd,J=5.0, 1.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.60-7.47 (m, 5H), 7.30-7.20 (m,2H), 7.02 (dd, J=7.4, 5.0 Hz, 1H).

N-[5-(4-{[3-(4-fluorophenyl)pyrazin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34mmol), 3-(4-fluorophenyl)pyrazin-2-amine (76 mg, 0.40 mmol), cesiumcarbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) weresuspended in 1,4-dioxane (3 mL). Reaction mixture was degassed withargon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours.After that time reaction mixture was cooled to room temperature,Filtered thru celite, evaporated and purified via column chromatographyusing DCM/MeOH 1:0→97:3 as a eluent to give product as a yellowish solid(68 mg, 49.8%). UPLC (254 nm): RT=5.88 min, 95.5% purity, [M+H]=407.05.

N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine(C9). To solution ofN-[5-(4-{[3-(4-fluorophenyl)pyrazin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide(68 mg, 0.17 mmol) in methanol (1 mL) concentrated hydrochloric acid (1mL) was added dropwise. Reaction mixture was refluxed overnight. Afterthis time reaction was diluted with saturated sodium bicarbonatesolution (20 mL), methanol was evaporated and extraction with ethylacetate (2×15 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with DCM/MeOH 9:1. Re-purification was performedvia preparative TLC eluted with DCM/MeOH 95:5 to give desired product asa yellow solid (20.2 mg, 33.2%). LCMS-Method 4(328 nm): RT=2.44 min,97.0% purity, [M+H]=365.15. ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s, 1H),8.19 (s, 2H), 7.86-7.79 (m, 2H), 7.64 (s, 4H), 7.46-7.27 (m, 4H).

N-[5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34mmol), 2-(4-phenoxyphenyl)aniline (105 mg, 0.40 mmol), cesium carbonate(219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) were suspended in1,4-dioxane (3 mL). Reaction mixture was degassed with argon flow over20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol)was added. Reaction was stirred at 100° C. for 72 hours. After that timereaction mixture was cooled to room temperature, Filtered thru celite,evaporated and purified via column chromatography using DCM/MeOH1:0→98:2 as a eluent to give product as a yellow solid (115 mg, 71.7%).UPLC (254 nm): RT=7.96 min, 88.6% purity, [M+H]=479.15.

5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine(C10). To solution ofN-[5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide(95 mg, 0.20 mmol) in methanol (1.4 mL) concentrated hydrochloric acid(1.4 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (20 mL), methanol was evaporated and extraction with ethylacetate (2×15 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with DCM/MeOH 8:2. Re-purification was performedvia preparative TLC eluted with Hex/EtOAc/MeOH 70:25:5 to give desiredproduct as a yellowish solid (17.2 mg, 19.9%). LCMS-Method 11 (200 nm):RT=3.57 min, 97.5% purity, [M+H]=437.16. ¹H NMR (300 MHz, Methanol-d₄) δ7.52-7.43 (m, 2H), 7.41-7.15 (m, 8H), 7.10-7.01 (m, 1H), 6.97-6.84 (m,4H), 6.82-6.72 (m, 2H).

N-[5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (120 mg, 0.40mmol), 2-(4-propoxyphenyl)aniline (110 mg, 0.48 mmol), cesium carbonate(262 mg, 0.80 mmol) and XantPhos (47 mg, 0.08 mmol) were suspended in1,4-dioxane (3.6 mL). Reaction mixture was degassed with argon flow over20 min and tris(dibenzylideneacetone)dipalladium(0) (33 mg, 0.04 mmol)was added. Reaction was stirred at 100° C. for 72 hours. After that timereaction mixture was cooled to room temperature, Filtered thru celite,evaporated and purified via column chromatography using DCM/MeOH1:0→97:3 as a eluent to give product as a yellowish solid (55.7 mg,31.1%). UPLC (254 nm): RT=8.07 min, 86.8% purity, [M+H]=445.30.

5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine(C11). To solution ofN-[5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide(56 mg, 0.13 mmol) in methanol (0.84 mL) concentrated hydrochloric acid(0.84 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (10 mL), methanol was evaporated and extraction with ethylacetate (2×10 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with Hex/EtOAc/MeOH 70:25:5. Re-purification wasperformed via maceration with diethyl ether to give desired product as alight brown solid (11 mg, 22%). LCMS-Method 4 (200 nm): RT=3.67 min,98.9% purity, [M+H]=403.19. ¹H NMR (300 MHz, Methanol-d₄) δ 7.56-7.47(m, 2H), 7.41-7.27 (m, 5H), 7.17 (td, J=7.3, 1.5 Hz, 1H), 6.96-6.81 (m,4H), 3.94 (t, J=6.5 Hz, 2H), 1.79 (dtd, J=13.8, 7.4, 6.4 Hz, 2H), 1.04(t, J=7.4 Hz, 3H).

N-{5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide.N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34mmol), 2-[4-(propan-2-yloxy)phenyl]aniline (91 mg, 0.40 mmol), cesiumcarbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) weresuspended in 1,4-dioxane (3 mL). Reaction mixture was degassed withargon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours.After that time reaction mixture was cooled to room temperature,Filtered thru celite, evaporated and purified via column chromatographyusing DCM/MeOH 1:0→97:3 as a eluent to give product as a yellowish solid(87.4 mg, 58.6%). UPLC (254 nm): RT=7.59 min, 87.6% purity,[M+H]=445.15.

5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine(C12). To solution ofN-{5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide(87 mg, 0.20 mmol) in methanol (1.3 mL) concentrated hydrochloric acid(1.3 mL) was added dropwise. Reaction mixture was refluxed overnight.After this time reaction was diluted with saturated sodium bicarbonatesolution (15 mL), methanol was evaporated and extraction with ethylacetate (2×15 mL) was made. Combined organic layers were dried oversodium sulfate, filtered and evaporated. Crude product was purified viapreparative TLC eluted with Hex/EtOAc/MeOH 70:25:5. Re-purification wasperformed via maceration with methanol, to give desired product as ayellow solid (7 mg, 8.8%). LCMS-Method 4 (200 nm): RT=3.54 min, 97.4%purity, [M+H]=403.20. ¹H NMR (300 MHz, Methanol-d₄) δ 7.55-7.47 (m, 2H),7.41-7.27 (m, 5H), 7.18 (td, J=7.3, 1.5 Hz, 1H), 6.94-6.81 (m, 4H), 4.59(dq, J=12.1, 6.1 Hz, 1H), 1.30 (d, J=6.0 Hz, 6H).

Synthesis Method E

To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (100 mg,0.52 mmol) and corresponding base (1.20 mmol, 2.3 eq) in 1,4-dioxane(3.0 mL) amine (1.0 eq) was added. Reaction mixture was degassed for 30minutes. Then xantphos (30 mg, 0.05 mmol) and corresponding catalystwere added and the mixture was stirred at 100° C. for 5 days. Thereaction mixture was filtrated throw cellite, the filtrate wasconcentrated and purified via column chromatography using 0-10% MeOH inDCM as eluent. Fractions containing the title compound were combined andconcentrated. Product was re-purified via P-TLC using 4% MeOH in DCM asan eluent.

4′-fluoro-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1′-biphenyl]-2-amine(D1) (34 mg, 19%). 4′-fluoro-[1,1′-biphenyl]-2-amine (97 mg, 0.52 mmol),t-BuONa (115 mg, 1.2 mmol), chloroform adduct oftris(dibenzylideneacetone)dipalladium(0) (26 mg 0.05 mmol),tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.05 mmol) were used.LCMS-Method 2 (200 nm): RT=5.54 min, 97.6% purity, [M+H]=345.15. ¹H NMR(300 MHz, DMSO-d₆) δ 8.46 (s, 1H), 7.82 (s, 1H), 7.45-7.49 (m, 4H),7.34-7.40 (m, 3H), 7.17-7.25 (m, 3H), 6.88 (d, J=9.0 Hz, 2H), 3.69 (s,3H).

3′,4′-dimethoxy-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1′-biphenyl]-2-amine(D2) (45 mg, 28%). 3′,4′-dimethoxy-[1,1′-biphenyl]-4-amine (120 mg, 0.52mmol), Cs₂CO₃ (396 mg, 1.2 mmol), chloroform adduct oftris(dibenzylideneacetone)dipalladium(0) (26 mg 0.05 mmol) were used.LCMS-Method 2 (200 nm) RT=4.8 min, 98.7% purity, [M+H]=387.14. ¹H NMR(300 MHz, DMSO-d₆) δ 8.46 (s, 1H), 7.74 (s, 1H), 7.47 (d, J=9 Hz, 2H),7.31-7.42 (m, 3H), 7.19-7.25 (m, 1H), 6.99 (d, 2H, J=6 Hz), 6.88 (d, 2H,J=9 Hz), 3.76 (s, 3H), 3.68 (s, 3H), 3.62 (s, 3H).

N-[2-(4-methoxyphenyl)phenyl]-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline(D3). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (73mg, 0.38 mmol) and Cs₂CO₃ (285 mg, 0.87 mmol) in 1,4-dioxane (2.25 mL)2-(4-methoxyphenyl)aniline (75 mg, 0.38 mmol) was added. Reactionmixture was degassed for 30 minutes. Then xantphos (22 mg, 0.04 mmol)and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (19 mg0.02 mmol) were added and the mixture was stirred at 100° C. overnight.The reaction mixture was filtrated through cellite, washed with MeOH.Filtrate was concentrated and purified via column chromatography using0-10% MeOH in DCM as eluent. Fractions containing the title compoundwere combined and concentrated. Product was re-purified via P-TLC using4% MeOH in DCM as an eluent to give desired product as an orange solid(13 mg, 10%). LCMS-Method 2 (200 nm): RT=5.38 min, 94.03% purity,[M+H]=357.21. ¹H NMR (300 MHz, Methanol-d₄) δ 8.48 (s, 1H), 7.45 (d,J=8.8 Hz, 2H), 7.39 (s, 1H), 7.37-7.28 (m, 4H), 7.29-7.13 (m, 1H), 6.94(dd, J=8.8, 3.3 Hz, 4H), 3.80 (s, 3H), 3.78 (s, 3H).

2-(4-methoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine(D4). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (68mg, 0.35 mmol) and 052003 (264 mg, 0.81 mmol) in 1,4-dioxane (2.10 mL)2-(4-methoxyphenyl)pyridin-3-amine (70 mg, 0.35 mmol) was added.Reaction mixture was degassed for 30 minutes. Then xantphos (20 mg, 0.03mmol) and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0)(18 mg 0.02 mmol) were added and the mixture was stirred at 100° C.overnight. The reaction mixture was filtrated through cellite, washedwith MeOH. Filtrate was concentrated and purified via columnchromatography using 0-10% MeOH in DCM as eluent. Fractions containingthe title compound were combined and concentrated. Product wasre-purified via P-TLC using 4% MeOH in DCM as an eluent to give desiredproduct as white solid (35 mg, 28%). LCMS-Method 1 (200 nm): RT=5.58min, 96.3% purity, [M+H]=358.22. ¹H NMR (300 MHz, DMSO-d₆) 8.67 (s, 1H),8.43 (d, J=5.9 Hz, 1H), 8.24 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.71 (d,J=8.8 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.39 (dd, J=8.1, 4.7 Hz, 3H),6.98 (t, J=9.1 Hz, 4H), 3.78 (s, 3H), 3.74 (s, 3H).

2-(4-fluorophenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine(D5). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (77mg, 0.40 mmol) and Cs₂CO₃ (301 mg, 0.92 mmol) in 1,4-dioxane (2.25 mL)2-(4-fluorophenyl)pyridin-3-amine (75 mg, 0.40 mmol) was added. Reactionmixture was degassed for 30 minutes. Then xantphos (23 mg, 0.04 mmol)and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (20 mg0.02 mmol) were added and the mixture was stirred at 100° C. overnight.The reaction mixture was filtrated through cellite, washed with MeOH.Filtrate was concentrated and purified via column chromatography using0-10% MeOH in DCM as eluent. Fractions containing the title compoundwere combined and concentrated. Product was re-purified via P-TLC using4% MeOH in DCM as an eluent to give desired product as light orangesolid (5 mg, 4%). LCMS-Method 1 (205 nm): RT=5.82 min, 99.46% purity,[M+H]=346.22. ¹H NMR (300 MHz, Methanol-d₄) δ 8.50 (s, 1H), 8.37 (dd,J=4.7, 1.5 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.70 (dd, J=9.1, 5.6 Hz,2H), 7.51 (d, J=8.8 Hz, 2H), 7.42 (dd, J=8.2, 4.7 Hz, 1H), 7.16 (t,J=8.7 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 3.78 (s, 3H).

4-(4-methyl-4H-1,2,4-triazol-3-yl)-N-[2-(4-phenoxyphenyl)phenyl]aniline(D6). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (74mg, 0.38 mmol) and Cs₂CO₃ (289 mg, 0.89 mmol) in 1,4-dioxane (3.00 mL)2-(4-phenoxyphenyl)aniline (100 mg, 0.38 mmol) was added. Reactionmixture was degassed for 30 minutes. Then xantphos (22 mg, 0.04 mmol)and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (20 mg0.02 mmol) were added and the mixture was stirred at 100° C. overnight.The reaction mixture was filtrated through celite, washed with MeOH.Filtrate was concentrated and purified via column chromatography using0-5% MeOH in DCM as eluent. Fractions containing the title compound werecombined and concentrated. Product was re-purified via P-TLC using 4%MeOH in DCM as an eluent to give desired product as white solid (25 mg,16%). LCMS-Method 5 (200 nm): RT=2.25 min, 99.51% purity, [M+H]=419.20.¹H NMR (300 MHz, Methanol-d₄) δ 8.47 (s, 1H), 7.74-7.14 (m, 11H), 7.09(t, J=7.9 Hz, 1H), 7.09-6.77 (m, 6H), 3.75 (s, 3H).

3-(3,4-dimethoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine(D7). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (59mg, 0.30 mmol) and Cs₂CO₃ (230 mg, 0.71 mmol) in 1,4-dioxane (2.10 mL)3-(3,4-dimethoxyphenyl)pyridin-4-amine (70 mg, 0.30 mmol) was added.Reaction mixture was degassed for 30 minutes. Then xantphos (18 mg, 0.03mmol) and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0)(16 mg 0.02 mmol) were added and the mixture was stirred at 100° C.overnight. The reaction mixture was filtrated through celite, washedwith MeOH. Filtrate was concentrated and purified via columnchromatography using 0-10% MeOH in DCM as eluent. Fractions containingthe title compound were combined and concentrated. Product wasre-purified via P-TLC using 4% MeOH in DCM as an eluent to give desiredproduct as white solid (20 mg, 16%). LCMS-Method 3 (305 nm): RT=2.69min, 98.21% purity, [M+H]=388.24. ¹H NMR (300 MHz, Methanol-d₄) δ 8.55(s, 1H), 8.26-8.19 (m, 2H), 7.72-7.58 (m, 2H), 7.43-7.25 (m, 3H), 7.09(d, J=4.2 Hz, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H).

Synthesis Method F

5-(3-bromopropyl)-1,3,4-thiadiazol-2-amine. Phosphoryl chloride (7.37mL, 79.0 mmol) was added to aminothiourea (2.185 g, 24.0 mmol) and4-bromobutanoic acid. The mixture was stirred at 85° C. overnight,cooled and poured into ice. Solution of saturated sodium biscarbonatewas added the solution and the water layer was extracted three timeswith EA (3×80 mL). Combined organic layers were dried over sodiumsulfate, filtered and evaporated. Crude product was purified via columnchromatography using 0-10% DCM in MeOH as eluent. Fractions containingthe title compound were combined and concentrated (3.301 g, 62%). UPLC(254 nm): RT=1.91 min, 68% purity, [M−H]=223.7.

N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide. To the solution of5-(3-bromopropyl)-1,3,4-thiadiazol-2-amine (3.3 g, 14.8 mmol) inanhydrous DCM (35 mL), under argon atmosphere, trietylamine (4.14 mL,29.7 mmol) and acetylchloride (1.16 mL, 16.3 mmol) were added. Reactionmixture was stirred for 6 hours at ambient temperature. After that time1M HCl was added (50 mL) and the water layer was extracted three timeswith DCM (3×80 mL). Combined organic layers were dried over sodiumsulfate, filtered, evaporated to provide the pure product (3.144 g,80%). UPLC (254 nm): RT=2.43 min, 89% purity, [M+H]=265.65.

N-[5-(3-azidopropyl)-1,3,4-thiadiazol-2-yl]acetamide. To the solution ofN-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide (1.0 g, 3.8 mmol)in anhydrous DMF (20.0 mL), under argon atmosphere, sodium azide (0.37g, 5.7 mmol) was added. Reaction mixture was stirred for 2 hours. Afterthat time water (10 mL) was added and the water layer was extracted withDCM (3×80 mL). Combined organic layers were dried over sodium sulfate,filtered and evaporated to provide the pure product (0.6 g, 71%). UPLC(254 nm): RT=2.29 min, 98% purity, [M+H]=227.0.

N-[5-(3-aminopropyl)-1,3,4-thiadiazol-2-yl]acetamide. Solution of methylN-[5-(3-azidopropyl)-1,3,4-thiadiazol-2-yl]acetamide (0.6 g, 2.7 mmol)in anhydrous tetrahydrofuran (7 mL was dropped to the suspension of LAHpellets (0.1 g, 2.8 mmol) in anhydrous THF (5 mL) under argonatmosphere. Reaction mixture was stirred 1 h at ambient temperature.After that time LAH (0.1 g, 2.8 mmol) was added. The stirring wascontinued for 2 hours. After that time 0.2 mL of water was added,followed by addition of 0.4 mL of 20% NaOH and 0.6 mL of water. Thesuspension was filtered throw cellite and washed with DCM/MeOH 9:1.Evaporation of solvents gave titled compound (0.22 g, 41%). UPLC (254nm): RT=1.17 min, 57% purity, [M−H]=201.2.

N-{5-[3-(4-fluorobenzenesulfonamido)propyl]-1,3,4-thiadiazol-2-yl}acetamide.To the solution of 3,4-dichlorobenzenosulfonyl chloride (165 mg, 0.85mmol) in the mixture of solvents DCM (1.0 mL) and pyridine (1.0 mL)N-[5-(3-aminopropyl)-1,3,4-thiadiazol-2-yl]acetamide (170 mg, 0.85 mmol)was added. The reaction mixture was stirred for 18 hours at ambienttemperature. After that time solvents were evaporated and to theresidues 1M HCl was added and the water layer was extracted with DCM(3×20 mL). Combined organic layers were dried over sodium sulfate,filtered, evaporated to provide the product (0.02 g, 7%). UPLC (254 nm):RT=2.56 min, 98% purity, [M+H]=358.85.

N-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]-4-fluorobenzene-1-sulfonamide(E2).N-{5-[3-(4-fluorobenzenesulfonamido)propyl]-1,3,4-thiadiazol-2-yl}acetamide(20 mg, 0.06 mmol) was dissolved in the solution of HCl (2 mL) and MeOH(2 mL). The reaction mixture was stirred for 18 hours at 80° C. Afterthat time solution of sodium biscarbonate was added and the water layerwas extracted with DCM (3×10 mL). Combined organic layers were driedover sodium sulfate, filtered and evaporated. Purification of crudeproduct via P-TLC using 4% methanol in dichloromethane as an eluent gavedesired product (3 mg, 17%). LCMS-Method 1 (200 nm): RT=2.56 min, 96.0%purity. [M+H]=317.15. ¹H NMR (300 MHz, MeOH-d₄) δ 7.87-7.94 (m, 2H),7.29-7.39 (m, 2H), 2.86-2.97 (m, 4H), 1.82-1.91 (m, 2H).

Synthesis Method G

N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide 2-chloroethylaminehydrochloride (0.25 g, 2.2 mmol), 4-fluorobenzenesulfonyl chloride (0.42g, 2.2 mmol), were dissolved in DCM (2.5 mL) and pyridine (2.5 mL).Reaction was stirred at room temperature overnight. The mixture wasdiluted with DCM (15.0 mL) and washed with 1M solution of hydrochloricacid (20 mL). Organic layer was dried over sodium sulfate, filtered andevaporated. Title compound was obtained as yellow oil (0.5 g, 86%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.82-7.95 (m, 2H), 7.25-7.33 (m, 2H),4.92 (t, 1H), 3.54-3.64 (t, 2H), 3.32-3.44 (dt, 2H).

N-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]ethyl}-4-fluorobenzene-1-sulfonamide(E3) N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide (0.18 g, 0.75mmol), 2-Amino-5-mercapto-1,3,4-thiadiazole (0.10 g, 0.75 mmol),potassium carbonate (0.31 g, 2.25 mmol) were dissolved in acetonitrile(2.0 mL) and stirred at 80° C. overnight. After that time reactionmixture was cooled to room temperature, filtered thru celite, evaporatedand purified via column chromatography using MeOH in DCM 0-5% as aluentto give pure product (120 mg, 48%) LCMS-Method 2 (200 nm): RT=4.24 min,99.71% purity, [M+H]=334.97, ¹H NMR (300 MHz, DMSO-d₆) δ 7.92 (br s,1H), 7.80-7.90 (m, 2H), 7.37-7.47 (m, 2H), 7.30 (br s, 2H), 3.07 (m,4H).

4-fluoro-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl}benzene-1-sulfonamide(G2) N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide (0.21 g, 0.87mmol), 3-mercapto-4-methyl-4H-1,2,4-triazole (0.10 g, 0.87 mmol),potassium carbonate (0.36 g, 2.61 mmol) were dissolved in acetonitrile(2.0 mL) and stirred at 80° C. overnight. After that time reactionmixture was cooled to room temperature, filtered thru celite, evaporatedand purified via column chromatography using MeOH in DCM 0-5% as eluentto give pure product (200 mg, 73%) LCMS-Method 2 (200 nm): RT=3.79 min,97.39% purity, [M+H]=317.05, 1H NMR (300 MHz, DMSO-d₆) δ 8.53 (s, 1H),7.97 (s, 1H), 7.88-7.77 (m, 2H), 7.49-7.35 (m, 2H), 3.53 (s, 3H),3.21-2.99 (m, 4H).

Synthesis Method H

N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide was synthesizedaccording to the procedure described for E2.

N-[5-(3-{[(4-fluorophenyl)(methyl)oxo-λ⁶-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-yl]acetamide.To the solution of (4-fluorophenyl)(imino)methyl-λ⁶-sulfanone (0.1 g,0.58 mmol) in anhydrous DMSO (4 mL), under argon atmosphere, KOH (0.065g, 1.15 mmol) was added. The suspension was stirred for 1.5 hours atambient temperature. After that time solution ofN-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide (0.229 g, 0.87mmol) in anhydrous DMSO (4 mL) was slowly (1.5 hours) dropped. Thereaction was quenched with water (5 mL) immediately after the droppingwas completed. The water layer was extracted with DCM (10 mL) and afterthat extracted 5 times with mixture of chloroform/isopropyl alcohol 3:1(5×20 mL). Combined organic layers were dried over sodium sulfate,filtered, evaporated to provide the pure product (0.06 g, 29%). UPLC(254 nm): RT=2.2 min, 61% purity, [M+H]=357.2

5-(3-{[(4-fluorophenyl)(methyl)oxo-λ⁶-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine(F2).N-[5-(3-{[(4-fluorophenyl)(methyl)oxo-λ⁶-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-yl]acetamide(20 mg, 0.06 mmol) was dissolved in the solution of HCl (2 mL) and MeOH(2 mL). The reaction mixture was stirred for 3 hours at 80° C. Afterthat time solution of sodium biscarbonate was added and the water layerwas extracted with DCM (3×10 mL). Combined organic layers were driedover sodium sulfate, filtered and evaporated. Purification of crudeproduct via P-TLC using 4% methanol in dichloromethane as an eluent gavedesired product (5 mg, 9%). LCMS (245 nm): RT=5.91 min, 98.88% purity.[M+H]=315.17 ¹H NMR (300 MHz, CDCl₃) δ 7.98-7.87 (m, 2H), 7.22-7.26 (m,2H), 5.21 (s, 2H), 3.11 (s, 2H), 2.89-3.09 (m, 2H), 1.97-2.00 (m, 2H).

Synthesis Method I

Methyl-4-(4-fluorobenzenesulfonamido)butanoate. To the solution of3,4-dichlorobenzenosulfonyl chloride (633 mg, 3.25 mmol) in DCM (3.0 mL)trietylamine (1.3 mL, 9.76 mmol) and methyl-4-aminobutanoatehydrochloride (500 mg, 3.25 mmol) was added. The reaction mixture wasstirred for 18 hours at ambient temperature. After that time 1M HCl (5mL) was added and the water layer was extracted with DCM (3×5 mL).Combined organic layers were dried over sodium sulfate, filtered,evaporated to provide the product (0.605 g, 68%). UPLC (254 nm): RT=2.89min, [M+H]=275.85.

4-Fluoro-N-[3-(hydrazinecarbonyl)propyl]benzene-1-sulfonamide. To thesolution of methyl-4-(4-fluorobenzenesulfonamido)butanoate (605 mg, 2.09mmol) in EtOH (10 mL) 50% hydrazine in H₂O (0.65 mL, 10.4 mmol) wasadded. Reaction mixture was stirred for 1 hour at 80° C. After that timethe reaction mixture was cooled, water (20 mL) was added and water layerwas extracted three times with EA (3×10 mL). Combined organic layerswere dried over sodium sulfate, filtered and evaporated to provide thepure product (180 mg, 31%). UPLC (254 nm): RT=1.88 min, 65% purity,[M+H]=276.2.

N-(3-{N′-[(1-dimethylamino)methylidene]hydrazinecarbonyl}propyl)-4-fluorobenzene-1-sulfonamide.To the solution of4-fluoro-N-[3-(hydrazinecarbonyl)propyl]benzene-1-sulfonamide (180 mg,0.65 mmol) in MeOH (2 mL) N,N-dimethylforamide dimethylacetal (78 mg,0.65 mmol) was added. Reaction mixture was stirred for 1 hour at 80° C.After that time solvent was evaporated to obtain desired product. (216mg, 100%). UPLC (254 nm): RT=1.78 min, 60% purity, [M+H]=331.3.

4-fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]benzene-1-sulfonamide(G1). MeNH₂ 2M in THF (32 mL, 3.3 mmol) was added to the solution ofN-(3-{N′-[(1-dimethylamino)methylidene]hydrazinecarbonyl}propyl)-4-fluorobenzene-1-sulfonamide(216 mg, 0.63 mmol) in anhydrous THF (5.0 mL) under argon atmosphere.Reaction mixture was cooled to 0° C. and acetic acid (2 mL) wascarefully added. Reaction mixture was stirred for 1 hour at 100° C.After that time reaction was cooled to room temperature and water (5 mL)was added and water layer was extracted three times with EA (3×20 mL).Combined organic layers were dried over sodium sulfate, filtered andevaporated. Crude product was purified via column chromatography using0-4% MeOH in DCM as eluent. Obtained 40 mg of product was re-purifiedvia P-TLC using 4% MeOH in DCM as an eluent and then re-purified viapreparative HPLC. Fraction containing the title compound in pure formwas concentrated (3 mg, 2%). LCMS-Method 1 (200 nm): RT=6.17 min, 99.5%purity, [M+H]=299.2. ¹H NMR (300 MHz, CDCl₃) δ 8.09 (s, 1H), 7.84-7.90(m, 2H), 7.15-7.23 (m, 2H), 5.62 (t, J=5.6 Hz, 1H), 3.64 (s, 3H), 3.12(q, J=3.1 Hz, 2H), 2.85 (t, J=6.6 Hz, 2H) 2.06-2.15 (m, 2H).

Synthesis Method K

N-(2-chloroethyl)sulfamoyl chloride 2-chloroethylamine hydrochloride(0.50 g, 4.3 mmol), sulfuryl chloride (3.49 g, 2.10 mL, 25.8 mmol), weredissolved in acetonitrile (5.0 mL) Reaction was stirred at 80° C.overnight. The mixture was concentrated and used directly into nextstep. Title compound was obtained as yellow oil (0.5 g, 86% yield). ¹HNMR (300 MHz, d₆-DMSO) δ 11.0 (bs, 1H), 3.83 (t, 2H), 3.36 (t, 2H)

(2-chloroethyl)[(3,4-dimethoxyphenyl)sulfamoyl]amineN-(2-chloroethyl)sulfamoyl chloride (0.14 g, 0.78 mmol) and3,4-dimethoxyaniline (0.12 g, 0.78 mmol) were dissolved in DCM (1.2 mL)and pyridine (1.2 mL). Reaction was stirred at room temperatureovernight. After that time reaction mixture was cooled to roomtemperature. The mixture was diluted with DCM (15.0 mL) and washed with1M solution of hydrochloric acid (20 mL). Organic layer was dried oversodium sulfate, filtered and evaporated. Title compound was obtained asyellow oil (0.23 g, 100% yield). Compound was used in the next stepwithout further purification. UPLC (280 nm): RT=3.14 min, 11% purity,[M+H]=294.95

[(3,4-dimethoxyphenyl)sulfamoyl]({2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl})amine(G5) (2-chloroethyl)[(3,4-dimethoxyphenyl)sulfamoyl]amine (0.085 g, 0.74mmol), 3-mercapto-4-methyl-4H-1,2,4-triazole (0.22 g, 0.74 mmol),potassium carbonate (0.31 g, 2.21 mmol) were dissolved in acetonitrile(1.7 mL) and stirred at 80° C. for 3 hours. After that time reactionmixture was cooled to room temperature, filtered thru celite, evaporatedand purified via column chromatography using MeOH in DCM 0-5% as eluentto give pure product (8 mg, 3%) LCMS-Method 2 (200 nm): RT=3.08 min,99.1% purity, [M+H]=374.03, 1H NMR (400 MHz, DMSO-d₆) δ 7.57 (s, 1H),6.96-6.75 (m, 2H), 6.72-6.63 (m, 1H), 3.71 (d, J=2.7 Hz, 6H), 3.51 (s,3H), 3.23-3.08 (m, 4H).

Synthesis Method L

[4-(4-fluorobenzenesulfonamido)phenyl]boronic acid 4-aminophenylboronicacid (1.5 g, 8.7 mmol), and 4-fluorophenylsulfonyl chloride (1.53 g, 7.9mmol) were dissolved in pyridine (43 mL). The mixture was stirred at 50°C. overnight, cooled to room temperature and solvent was removed invacuo. Crude product was used in next step without any furtherpurification (5.4 g, 200%). UPLC (254 nm): RT=2.88 min, 50% purity,[M-2H]=293.5.

[4-(3,4-dimethoxybenzenesulfonamido)phenyl]boronic acid4-aminophenylboronic acid (2.35 g, 11.6 mmol), and3,4-dimethoxyphenylsulfonyl chloride (1.53 g, 7.9 mmol) were dissolvedin pyridine (80 mL). The mixture was stirred at 50° C. overnight, cooledto room temperature and solvent was removed in vacuo. Crude product wasused in next step without any further purification (8.1 g, 200%). UPLC(254 nm): RT=2.77 min, 50% purity, [M-2H]=335.6.

N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide(11). Solution of [4-(4-fluorobenzenesulfonamido)phenyl]boronic acid(2.75 g, 9.2 mmol), 2-amino-5-bromo-thiazole hydrobromide (2.00 g, 7.7mmol) and potassium carbonate (3.21 g, 23.1 mmol) in 1,4-dioxane (40.0mL) and water (4.0 mL) was degassed with argon flow over 20 min and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(11) complex withdichloromethane (0.84 g, 1.2 mmol) was added as one portion. Reactionmixture was stirred overnight at 130° C. After this time reaction wasfiltered thru celite, which was washed with DCM, water (40 mL) wasadded, layers were separated and water layer was extracted three withDCM (3×25 mL), organic layers were combined, dried over sodium sulfate,filtered and evaporated. Crude product was purified via columnchromatography using Methanol in DCM (0-3%) as eluent, and fractioncontaining product was additional re-purified via preparative HPLCmethod to give the pure product as red solid (48 mg, 2%). LCMS-Method 1(254 nm): RT=6.73 min, 99.6% purity, [M+H]=349.7. ¹H NMR (300 MHz,DMSO-d₆) δ 10.36 (s, 1H), 7.84-7.76 (m, 2H), 7.45-7.36 (m, 2H), 7.28(dd, J=6.6, 2.0 Hz, 3H), 7.14-6.97 (m, 4H).

N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide(12). Solution [4-(3,4-dimethoxybenzenesulfonamido)phenyl]boronic acid(1.64 g, 5.5 mmol), 2-amino-5-bromo-thiazole hydrobromide (1.20 g, 4.6mmol) and potassium carbonate (3.21 g, 23.1 mmol) in 1,4-dioxane (40.0mL) and water (4.0 mL) was degassed with argon flow over min and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(11) complex withdichloromethane (0.51 g, 0.7 mmol) was added as one portion. Reactionmixture was stirred overnight at 130° C. After this time reaction wasfiltered thru celite, which was washed with DCM, water (40 mL) wasadded, layers were separated and water layer was extracted three withDCM (3×25 mL), organic layers were combined, dried over sodium sulfate,filtered and evaporated. Crude product was purified via columnchromatography using Methanol in DCM (0-3%) as eluent, and fractioncontaining product was additional re-purified via preparative HPLCmethod to give the pure product as orange solid (45 mg, 3%). LCMS-Method2(200 nm): RT=2.99 min, 99.9% purity, [M+H]=392.0. ¹H NMR (300 MHz,DMSO-d₆) δ 8.16 (s, 1H), 7.34-7.22 (m, 5H), 7.13-6.95 (m, 5H), 3.79 (s,3H), 3.76 (s, 3H).

Synthesis Method M

2-bromo-4′-fluoro-1,1′-biphenyl Solution of 1,2-dibromobenzene (8.26 g,35.0 mmol), 4-flurophenylboronic acid (2.5 g, 17.9 mmol) and sodiumcarbonate (3.79 g, 35.0 mmol) in ethanol (35.0 mL), toluene (35.0 mL)and water (35.0 mL) was degassed with argon flow over 20 min andtetrakis(triphenylphosphine) palladium(0) (1.00 g, 0.9 mmol) was addedas one portion. Reaction mixture was stirred overnight at 100° C. Afterthis time reaction was filtered thru celite, layers were separated andwater layer was extracted twice with ethyl acetate (2×15 mL), organiclayers were combined, dried over sodium sulfate, filtered andevaporated. Crude product was purified via column chromatography usinghexanes as eluent to give the title product (5.50 g, 122%). UPLC (254nm): RT=4.33 min, 91% purity, [M+H]=not observed.

1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidine-4-carbonitrile Solution of2-bromo-4′-fluoro-1,1′-biphenyl (0.3 g, 1.2 mmol),piperidine-4-carbonitrile (0.2 g, 1.8 mmol), XantPhos (0.14 g, 0.24mmol) and cesium carbonate (0.78 g, 2.4 mmol) in anhydrous 1,4-dioxane(3.0 mL), was degassed with argon flow over 20 min andtris(dibenzylideneacetone)dipalladium(0) (0.11 g, 0.12 mmol) was addedas one portion. Reaction mixture was stirred overnight at 100° C. Afterthis time reaction was filtered thru celite, washed with ethyl acetateand evaporated. Crude product was purified via column chromatographyusing ethyl acetate in hexanes (0-4%) as eluent to give the titleproduct (0.18 g, 54%). UPLC (254 nm): RT=4.25 min, 90% purity,[M+H]=281.4.

5-(1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine(L2) Solution of1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidine-4-carbonitrile (0.18 g, 0.7mmol) and thiosemicarbazide (0.09 g, 1.05 mmol) trifluoroacetic acid(1.5 mL) was stirred at 65° C. over 2 hours. After this time reactionwas cooled to room temperature diluted with saturated sodium bicarbonatesolution (15 mL) and extracted with DCM (3×15 mL), organic layers werecombined, dried over sodium sulfate, filtered and evaporated. Crudeproduct was triturated with ethyl acetate (1 mL) filtered off and driedunder vacuum to give pure product (100 mg, 45%) LCMS (LCMS method:LCMS-002-20-80-95-12-05-25 (Gemini-BCM)-UV, 200 nm): RT=4.97 min, 96.7%purity, [M+H]=355.2. ¹H NMR (300 MHz, DMSO-d₆) δ 7.70-7.58 (m, 2H),7.38-7.17 (m, 4H), 7.16-6.89 (m, 4H), 3.05 (d, J=11.8 Hz, 2H), 2.87(ddd, J=11.5, 7.6, 3.9 Hz, 1H), 2.62 (t, J=11.3 Hz, 2H), 1.86 (d, J=12.7Hz, 2H), 1.54 (qd, J=12.0, 3.8 Hz, 2H).

Synthesis Method N

tert-Butyl-4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate wassynthesized in two steps according to the literature (overall yield:60%).

tert-Butyl-4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate. Tothe solution oftert-butyl-4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate (3.75 g,13.23 mmol) in anhydrous DCM (35 mL), under argon atmosphere,trietylamine (3.69 mL, 26.4 mmol) and acetylchloride (1.00 mL, 14.6mmol) were added. Reaction mixture was stirred for 48 hours at ambienttemperature. After that time water was added (50 mL) and the water layerwas extracted five times with DCM (5×80 mL). Combined organic layerswere dried over sodium sulfate, filtered and evaporated to provide thepure product (4.175 g, 97%). UPLC (254 nm): RT=4.27 min, [M+H]=326.25.

N-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]acetamide. To the solution oftert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate(4.175 g, 12.83 mmol) in THF (90.0 mL), 4M HCl in dioxane (10 mL) wasadded. Reaction mixture was stirred for 18 hours. After that timereaction mixture was filtered, the precipitation was washed with EA(2×40 mL) and dried under reduced pressure to give pure product (2.752g, 82%). UPLC (254 nm): RT=2.1 min, [M+H]=226.25.

N-{5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide.To a solution of 3,4-dichlorobenzenosulfonyl chloride (182 mg, 0.94mmol) in the mixture of solvents DCM (3.0 mL) and pyridine (3.0 mL)N-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]acetamide (211 mg, 0.94 mmol) wasadded. The reaction mixture was stirred for 48 hours at ambienttemperature. After that time solvents were evaporated and crude wastaken to the next step.

5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-amine (M1).N-{5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide(300 mg, 0.78 mmol) was dissolved in the solution of HCl (12 mL) andMeOH (12 mL). The reaction mixture was stirred for 18 hours at 80° C.After that time solution of saturated sodium biscarbonate was added andthe water layer was extracted with DCM (3×10 mL). Combined organiclayers were dried over sodium sulfate, filtered, evaporated and purifiedvia column chromatography using 0-10% MeOH in DCM as eluent. Fractionscontaining the title compound were combined and concentrated. Productwas re-purified via P-TLC using 4% MeOH in DCM as an eluent (16 mg, 6%).LCMS-Method 1 (220 nm): RT=6.37 min, 95.99% purity, [M+H]=342.07. ¹H NMR(300 MHz, CD₃OD) δ 7.85-7.90 (m, 2H), 7.35-7.41 (m, 2H), 6.7 (s, 1H),3.82 (d, J=12.0 Hz, 2H), 2.61-2.73 (m, 1H), 2.40-2.49 (m, 2H), 1.98-2.04(m, 2H), 1.60-1.75 (m, 2H).

1-(4-fluorobenzenesulfonyl)piperidine-4-carbonitrile. To a solution ofpiperidine-4-carbonitrile (500 mg, 4.54 mmol) in the mixture of solventsDCM (5.0 mL) and pyridine 4-4luorobenzenesulfonyl chloride (880 mg, 4.54mmol) was added. The reaction mixture was stirred for 16 hours atambient temperature. Reaction mixture was diluted with 1M HCl (50 ml)and DCM (50 ml) and layers were separated. Organic layer was washedtwice with 1M HCl (2×50 ml) and concentrated to give desired product asbeige solid. ¹H NMR (400 MHz, Chloroform-d) δ 7.98-7.66 (m, 2H),7.36-7.12 (m, 2H), 3.29-3.06 (m, 4H), 2.91-2.71 (m, 1H), 2.17-1.89 (m,4H).

5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-amine(M2). 1-(4-fluorobenzenesulfonyl)piperidine-4-carbonitrile (500 mg, 1.86mmol) and thisemicarbazide (190 mg, 2.05 mmol) were dissolved in TFA(4.0 mL) and the reaction mixture was stirred for 2 hours at 60° C.After that time solvent was concentrated and residue was suspended inDCM:MeOH (4.0 ml, 95:5; vol:vol) solution and precipitate was filteredto afford desired compound as white solid (610 mg, 96.0%). LCMS-Method 2(method: LCMS Method 2 (Gemini BCM)-UV, 200 nm): RT=4.29 min, 97.59%purity, [M+H]=343.13. ¹H NMR (300 MHz, DMSO-d₆) δ 8.20-7.71 (m, 2H),7.51 (t, J=8.8 Hz, 2H), 3.66 (dt, J=12.2, 3.7 Hz, 2H), 2.95 (ddd,J=11.3, 7.5, 3.8 Hz, 1H), 2.43 (dd, J=11.8, 2.6 Hz, 2H), 2.10-1.91 (m,2H), 1.76-1.43 (m, 2H).

Synthesis Method O

tert-butyl4-{N′-[(1E)-(dimethylamino)methylidene]hydrazinecarbonyl}piperidine-1-carboxylate.To the solution tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate(500 mg, 2.05 mmol) in DMF (5 mL) N,N-dimethylforamide dimethylacetal(245 mg, 2.05 mmol) was added. Reaction mixture was stirred for 18 hourat 100° C. After that time solvent was evaporated to obtain desiredproduct (601 mg, 98%).

tert-butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate.MeNH₂ 2M in THF (15 mL, 40.2 mmol) was added to the solution oftert-butyl4-{N′-[(1E)-(dimethylamino)methylidene]hydrazinecarbonyl}piperidine-1-carboxylate(600 mg, 2.01 mmol) in anhydrous THF (6.0 mL) under argon atmosphere.Reaction mixture was cooled to 0° C. and acetic acid (2 mL) wascarefully added. Reaction mixture was stirred for 18 hour at 100° C.After that time reaction was cooled to room temperature and water (20mL) was added and water layer was extracted three times with EA (3×50mL). Combined organic layers were dried over sodium sulfate, filteredand evaporated to give crude compound (511 mg, 95%).

4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine. To the solution oftert-butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate(511 mg, 1.71 mmol) in THF (5.0 mL), 4M HCl in dioxane (6.0 mL) wasadded. Reaction mixture was stirred for 18 hours. After that timereaction mixture was filtered, the precipitate was washed with EA (2×40mL) and dried under reduced pressure to give product (347 mg, 100%).

1-(4-fluorobenzenesulfonyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine(N1). To a solution of 4-fluorobenzenosulfonyl chloride (117 mg, 0.60mmol) in pyridine (1.0 mL) 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine(100 mg, 0.60 mmol) was added. The reaction mixture was stirred for 18hours at ambient temperature. After that time solvent was evaporated and1 M HCl (5 mL) was added and the water layer was extracted with DCM(3×10 mL). Combined organic layers were dried over sodium sulfate,filtered and evaporated. Product was purified via P-TLC using 5% MeOH inDCM as an eluent (6 mg, 3%). LCMS-Method 2 (220 nm): RT=3.63 min, 96.34%purity, [M+H]=325.11 ¹H NMR (300 MHz, CDCl₃) δ 8.05 (s, 1H), 7.77-7.90(m, 2H), 7.20-7.28 (m, 2H), 7.78-7.83 (m, 1H), 3.62 (s, 3H), 2.60-2.86(m, 4H), 2.02-2.15 (m, 4H).

Synthesis Method P

tert-butyl 5-methyl-1H-1,3-benzodiazole-1-carboxylate5-methyl-1H-1,3-benzodiazole (0.5 g, 7.6 mmol), Boc anhydride (2.44 g,11.4 mmol), DMAP (92 mg, 0.76 mmol) and triethylamine (2.11 mL, 15 mmol)were dissolved in acetonitrile (10 mL). The mixture was stirred at 80°C. overnight, cooled and solvent was removed in vacuo. Crude product waspurified via column chromatography using DCM as eluent. Fractionscontaining the title compound were combined and concentrated (0.80 g,46%). UPLC (254 nm): RT=3.75 min, 93.2% purity, [M+H]=233.2.

tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate. tert-butyl5-methyl-1H-1,3-benzodiazole-1-carboxylate (0.8 g, 3.44 mmol),N-bromosuccimide (0.64 g, 3.62 mmol), dibenzoyl peroxide (22 mg, 0.1mmol) were suspended in tetrachloromethane (16 ml), Reaction mixture wasstirred overnight at 90° C. After that time reaction mixture was cooledto 0° C., precipitate was filtered off and filtrate was concentrated invacuo to give desired product as pale yellow oil. (0.95 g, 89%). UPLC(254 nm): RT=3.75 min, 80% purity, [M+H]=312.75.

4′-fluoro-[1,1′-biphenyl]-2-amine. Solution of 2-bromoaniline (1.5 g,8.7 mmol), 4-flurophenylboronic acid (1.46 g, 10.5 mmol) and potassiumcarbonate (4.16 g, 30.1 mmol) in 1,4-dioxane (15.0 mL) and water (15.0mL) was degassed with argon flow over 20 min and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.43 g, 0.5 mmol) was added as one portion. Reactionmixture was stirred overnight at 100° C. After this time reaction wasfiltered thru celite, layers were separated and water layer wasextracted twice with ethyl acetate (2×15 mL), organic layers werecombined, dried over sodium sulfate, filtered and evaporated. Crudeproduct was purified via column chromatography using 10% ethyl acetatein hexanes as eluent to give the pure product (1.65 g, 100%). UPLC (254nm): RT=3.31 min, 99% purity, [M+H]=187.9.

N-[(1H-1,3-benzodiazol-5-yl)methyl]-4′-fluoro-[1,1′-biphenyl]-2-amine(O1). To the solution of 4′-fluoro-[1,1′-biphenyl]-2-amine (100 mg, 0.53mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate(244 mg, 0.59 mmol) in DMF (1.0 mL) sodium carbonate (170 mg, 1.6 mmol)was added. The reaction mixture was stirred overnight at 80° C. Afterthat time reaction mixture was diluted with ethyl acetate (15.0 mL) andwashed with semi-saturated brine (3×20 mL). Organic layer were driedover sodium sulfate, filtered, evaporated to provide the crude product,which was purified via column chromatography using MeOH in DCM 0-2% asan eluent to give desired product as off white solid (48 mg, 22%)LCMS-Method 2 (200 nm): RT=4.13 min, 97.2% purity, [M+H]=318.25. ¹H NMR(300 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.62-7.43 (m, 3H), 7.32 (t, J=8.9 Hz,2H), 7.18 (d, J=8.2 Hz, 1H), 7.05 (ddd, J=8.5, 7.4, 1.6 Hz, 1H), 6.97(dd, J=7.5, 1.6 Hz, 1H), 6.70-6.44 (m, 2H), 5.32 (s, 1H), 4.40 (d, J=5.9Hz, 2H).

3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine. Solution of 2-bromoaniline (3.0g, 17.4 mmol), 3,4-dimethoxyphenylboronic acid (3.81 g, 20.9 mmol) andpotassium carbonate (8.32 g, 30.1 mmol) in 1,4-dioxane (30.0 mL) andwater (30.0 mL) was degassed with argon flow over 20 min and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.85 g, 1.1 mmol) was added as one portion. Reactionmixture was stirred overnight at 100° C. After this time reaction wasfiltered thru celite, layers were separated and water layer wasextracted twice with ethyl acetate (2×15 mL), organic layers werecombined, dried over sodium sulfate, filtered and evaporated. Crudeproduct was purified via column chromatography using ethyl acetate inhexanes 2-10% as eluent to give the pure product (3.2 g, 80%). UPLC (254nm): RT=3.25 min, 90% purity, [M+H]=229.9.

N-[(1H-1,3-benzodiazol-5-yl)methyl]-3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine(O2). To the solution of 3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine (200mg, 0.87 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (0.398 g, 0.96 mmol)in DMF (1.0 mL) sodium carbonate (277 mg, 2.62 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was diluted with ethyl acetate (15.0 mL) and washedwith semi-saturated brine (3×20 mL). Organic layer were dried oversodium sulfate, filtered, evaporated to provide the crude product, whichwas purified via column chromatography using MeOH in DCM 0-2% as aneluent to give desired product as off white solid (70 mg, 17%)LCMS-Method 2 (205 nm): RT=3.66 min, 96.5% purity, [M+H]=360.1. ¹H NMR(300 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.20 (dd,J=8.3, 1.6 Hz, 1H), 7.12-6.87 (m, 5H), 6.61 (ddd, J=8.3, 5.9, 1.2 Hz,2H), 5.26 (t, J=5.9 Hz, 1H), 4.40 (d, J=5.9 Hz, 2H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline (O3). Tothe solution of 2-(4-methoxyphenyl)aniline (90 mg, 0.45 mmol) andtert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (156 mg,0.50 mmol) in DMF (1.0 mL) sodium carbonate (144 mg, 1.36 mmol) wasadded. The reaction mixture was stirred overnight at 80° C. After thattime reaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 100:0→98:2. Re-purification was performed via preparative TLCeluted with DCM/MeOH 95:5 to give desired product as off white solid (35mg, 23%). LCMS-Method 2 (230 nm): RT=3.90 min, 96.6% purity,[M+H]=330.24. ¹H NMR (300 MHz, Methanol-d₄) δ 8.13 (s, 1H), 7.56 (d,J=5.5 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.25 (dd, J=8.4, 1.2 Hz, 1H),7.15-6.93 (m, 4H), 6.75-6.63 (m, 2H), 4.45 (s, 2H), 3.84 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine(O4). To the solution of 2-(4-methoxyphenyl)pyridin-3-amine (90 mg, 0.45mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate(155 mg, 0.50 mmol) in DMF (1.0 mL) sodium carbonate (143 mg, 1.36 mmol)was added. The reaction mixture was stirred overnight at 80° C. Afterthat time reaction mixture was cooled down to RT and filtered throughcelite. Celite pad was washed with MeOH. Filtrate was evaporated toprovide the crude product, which was purified via column chromatographyusing DCM/MeOH/NH₃ 100:0:0→9:1:0.1. Re-purification was performed viapreparative TLC eluted with DCM/MeOH/NH₃ 95:5:0.1 to give desiredproduct as off white solid (10 mg, 7%). LCMS-Method 1 (205 nm): RT=4.66min, 97.8% purity, [M+H]=331.27. ¹H NMR (300 MHz, Methanol-d₄) δ 8.14(s, 1H), 7.81 (d, J=5.7 Hz, 1H), 7.58 (t, J=3.9 Hz, 4H), 7.27 (d, J=9.6Hz, 1H), 7.20-6.97 (m, 4H), 4.49 (s, 2H), 3.86 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine(O5). To the solution of 3-(4-methoxyphenyl)pyridin-2-amine (100 mg,0.50 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (202 mg, 0.65 mmol) inDMF (1.0 mL) sodium carbonate (159 mg, 1.50 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH/NH₃ 95:5:0→9:1:0.1. Re-purification was performed viapreparative TLC eluted with DCM/MeOH/NH₃ 95:5:0→9:1:0.1 to give desiredproduct as white solid (4 mg, 2.5%). LCMS-Method 3 (200 nm): RT=2.66min, 96.3% purity, [M+H]=331.11. ¹H NMR (300 MHz, Methanol-d₄) δ 8.12(s, 1H), 7.97 (dd, J=5.2, 1.8 Hz, 1H), 7.62-7.51 (m, 2H), 7.35 (t, J=8.7Hz, 3H), 7.25 (d, J=9.7 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.69 (dd,J=7.2, 5.2 Hz, 1H), 4.69 (s, 2H), 3.83 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine(O6). To the solution of 3-(4-methoxyphenyl)pyridin-4-amine (100 mg,0.50 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (172 mg, 0.55 mmol) inDMF (1.0 mL) sodium carbonate (159 mg, 1.50 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH/NH₃ 95:5:0→9:1:0.1. Re-purification was performed viapreparative TLC eluted with DCM/MeOH/NH₃ 95:5:0→9:1:0.1 to give desiredproduct as white solid (12 mg, 7%). LCMS-Method 3 (245 nm): RT=2.36 min,97.4% purity, [M+H]=331.25. ¹H NMR (300 MHz, Methanol-d₄) δ 8.28 (s,1H), 8.26-8.18 (m, 2H), 7.77-7.67 (m, 2H), 7.42-7.32 (m, 3H), 7.11 (d,J=6.7 Hz, 2H), 6.98 (d, J=7.1 Hz, 1H), 5.52 (s, 2H), 3.87 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine 07.To the solution of 4-(4-methoxyphenyl)pyridin-3-amine (100 mg, 0.50mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate(172 mg, 0.55 mmol) in DMF (1.0 mL) sodium carbonate (159 mg, 1.50 mmol)was added. The reaction mixture was stirred overnight at 80° C. Afterthat time reaction mixture was cooled down to RT and filtered throughcelite. Celite pad was washed with MeOH. Filtrate was evaporated toprovide the crude product, which was purified via column chromatographyusing DCM/MeOH/NH₃ 95:5:0→9:1:0.1. Re-purification was performed viapreparative HPLC to give desired product as white solid (5 mg, 4%). LCMS(LCMS-Method 3, 245 nm): RT=2.43 min, 73.7% purity, [M+H]=331.25. ¹H NMR(300 MHz, Methanol-d₄) δ 8.36 (s, 1H), 8.30 (s, 1H), 8.23 (d, J=6.0 Hz,1H), 7.91 (s, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.67-7.51 (m, 4H), 7.44 (d,J=8.3 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 1H), 5.77 (s,2H), 3.88 (s, 3H).

N-(1H-1,3-benzodiazol-5-yl methyl)-5-(4-methoxyphenyl)pyrimidin-4-amine(O8). To the solution of 5-(4-methoxyphenyl)pyrimidin-4-amine (50 mg,0.25 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (86 mg, 0.28 mmol) inDMF (0.5 mL) sodium carbonate (79 mg, 0.75 mmol) was added. The reactionmixture was stirred overnight at 80° C. After that time reaction mixturewas cooled down to RT and filtered through celite. Celite pad was washedwith MeOH. Filtrate was evaporated to provide the crude product, whichwas purified via preparative HPLC to give desired product as yellowishsolid (1.96 mg, 1.8%). LCMS-Method 12 (200 nm): RT=4.5 min, 100.0%purity, [M+H]=332.20. ¹H NMR (300 MHz, Methanol-d₄) δ 8.86 (d, J=1.9 Hz,1H), 8.30 (s, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J=8.3Hz, 1H), 7.44-7.35 (m, 3H), 7.14-7.06 (m, 2H), 5.51 (s, 2H), 3.87 (s,3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine(O9). To the solution of 3-(4-methoxyphenyl)pyrazin-2-amine (140 mg,0.70 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (240 mg, 0.77 mmol) inDMF (1.0 mL) sodium carbonate (221 mg, 2.09 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH/NH₃ 95:5:0→9:1:0.1. Re-purification was performed viapreparative TLC eluted with DCM/MeOH/NH₃ 95:5:0→9:1:0.1 to give desiredproduct as off white solid (5 mg, 2%). LCMS-Method 3 (270 nm): RT=3.04min, 87.4% purity, [M+H]=332.24. ¹H NMR (300 MHz, Methanol-d₄) δ 8.13(s, 1H), 7.96 (d, J=2.9 Hz, 1H), 7.76 (d, J=2.9 Hz, 1H), 7.58 (dd,J=12.8, 8.6 Hz, 4H), 7.29 (dd, J=8.3, 1.4 Hz, 1H), 7.09 (d, J=8.8 Hz,2H), 4.73 (s, 2H), 3.86 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine(O10). To the solution of 3-(3,4-dimethoxyphenyl)pyridin-4-amine (100mg, 0.43 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (214 mg, 0.69 mmol) inDMF (1.0 mL) sodium carbonate (137 mg, 1.30 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 95:5→9:1. Fractions containing product were collected andevaporated. Residue was suspended in MeOH and filtered to give desiredproduct as white solid (11 mg, 7%). LCMS-Method 9 (200 nm): RT=2.8 min,95.2% purity, [M+H]=361.16. ¹H NMR (300 MHz, Methanol-d₄) δ 8.28 (d,J=2.2 Hz, 2H), 8.21 (dd, J=7.2, 1.9 Hz, 1H), 7.75 (s, 2H), 7.37 (dd,J=8.4, 1.5 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.07-6.94 (m, 3H), 5.52 (s,2H), 3.90 (s, 3H), 3.88 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine(O11). To the solution of 3-(3,4-dimethoxyphenyl)pyridin-2-amine (100mg, 0.43 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (150 mg, 0.48 mmol) inDMF (1.0 mL) sodium carbonate (138 mg, 1.30 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH/NH₃ 95:5:0→9:1:0.1. Re-purification was performed viapreparative TLC eluted with DCM/MeOH/NH₃ 95:5:0→9:1:0.1 to give desiredproduct as off white solid (11 mg, 7%). LCMS-Method 1 (200 nm): RT=4.98min, 93.2% purity, [M+H]=361.25. ¹H NMR (300 MHz, Methanol-d₄) δ 8.13(s, 1H), 7.98 (dd, J=5.2, 1.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 2H), 7.37 (dd,J=7.2, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 7.09-6.91 (m, 3H),6.69 (dd, J=7.2, 5.2 Hz, 1H), 4.70 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine(O12). To the solution of 3-(3,4-dimethoxyphenyl)pyrazin-2-amine (100mg, 0.43 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (175 mg, 0.56 mmol) inDMF (1.0 mL) sodium carbonate (137 mg, 1.30 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH/NH₃ 95:5:0→9:1:0.1. Re-purification was performed viapreparative TLC eluted with DCM/MeOH/NH₃ 95:5:0→9:1:0.1 to give desiredproduct as off white solid (8 mg, 5%). LCMS-Method 3 (200 nm): RT=2.97min, 87.7% purity, [M+H]=362.21. ¹H NMR (300 MHz, Methanol-d₄) δ 8.14(s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 7.65-7.44 (m,2H), 7.37-7.20 (m, 3H), 7.09 (d, J=8.2 Hz, 1H), 4.73 (s, 2H), 3.89 (s,3H), 3.85 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine(O13). To the solution of 2-(4-fluorophenyl)pyridin-3-amine (110 mg,0.58 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (202 mg, 0.65 mmol) inDMF (1.0 mL) sodium carbonate (186 mg, 1.75 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH/NH₃ 95:5:0→9:1:0.1. Re-purification was performed viapreparative TLC eluted with DCM/MeOH/NH₃ 95:5:0→9:1:0.1 to give desiredproduct as off white solid (8 mg, 4%). LCMS-Method 1 (200 nm): RT=3.04min, 96.1% purity, [M+H]=319.23. ¹H NMR (300 MHz, ¹H NMR (300 MHz) δ8.20 (s, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.77-7.51 (m, 4H), 7.30 (t, J=8.6Hz, 3H), 7.23-7.01 (m, 2H), 4.53 (s, 2H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine(O14). To the solution of 3-(4-fluorophenyl)pyridin-2-amine (70 mg, 0.37mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate(128 mg, 0.41 mmol) in DMF (0.7 mL) sodium carbonate (118 mg, 1.12 mmol)was added. The reaction mixture was stirred overnight at 80° C. Afterthat time reaction mixture was cooled down to RT and filtered throughcelite. Celite pad was washed with MeOH. Filtrate was evaporated toprovide the crude product, which was purified via preparative HPLC.Re-purification was performed via preparative TLC eluted withDCM/MeOH/NH₃ 95:5:0.1 to give desired product as a white solid (7.7 mg,4.95%). LCMS-Method 1 (200 nm): RT=5.04 min, 97.1% purity, [M+H]=319.23.¹H NMR (300 MHz, Methanol-d₄) δ 8.09 (s, 1H), 8.00 (dd, J=5.2, 1.8 Hz,1H), 7.58-7.41 (m, 4H), 7.34 (dd, J=7.2, 1.8 Hz, 1H), 7.25-7.14 (m, 3H),6.70 (dd, J=7.2, 5.2 Hz, 1H), 4.69 (s, 2H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine(O15). To the solution of 3-(4-fluorophenyl)pyrazin-2-amine (100 mg,0.53 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (214 mg, 0.69 mmol) inDMF (1.0 mL) sodium carbonate (137 mg, 1.30 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH/NH₃ 95:5:0→9:1:0.1. Re-purification was performed viapreparative TLC eluted with DCM/MeOH/NH₃ 95:5:0→9:1:0.1 to give desiredproduct as off white solid (3 mg, 2%). LCMS-Method 1 (202 nm): RT=3.08min, 95.4% purity, [M+H]=320.22. ¹H NMR (300 MHz, Methanol-d₄) δ 8.13(s, 1H), 8.00 (d, J=2.8 Hz, 1H), 7.79 (d, J=2.8 Hz, 1H), 7.70 (dd,J=8.8, 5.4 Hz, 2H), 7.62-7.51 (m, 2H), 7.33-7.23 (m, 3H), 4.73 (s, 2H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline (O16). Tothe solution of 2-(4-phenoxyphenyl)aniline (100 mg, 0.38 mmol) andtert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (132 mg,0.42 mmol) in DMF (1.0 mL) sodium carbonate (122 mg, 1.15 mmol) wasadded. The reaction mixture was stirred overnight at 80° C. After thattime reaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 1:0→96:4. Re-purification was performed via preparative TLCeluted with DCM/MeOH/NH₃ 95:5:0.1 to give desired product as a whitesolid (25 mg, 16.7%). LCMS-Method 2 (205 nm): RT=4.99 min, 99.6% purity,[M+H]=392.26. ¹H NMR (300 MHz, Methanol-d₄) δ 8.13 (s, 1H), 7.57 (d,J=8.1 Hz, 2H), 7.47-7.33 (m, 4H), 7.27 (dd, J=8.5, 1.5 Hz, 1H),7.17-7.02 (m, 7H), 6.71 (ddd, J=7.8, 6.2, 1.2 Hz, 2H), 4.48 (s, 2H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline(O17). To the solution of 2-[4-(cyclohexyloxy)phenyl]aniline (100 mg,0.37 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (129 mg, 0.42 mmol) inDMF (1.0 mL) sodium carbonate (119 mg, 1.12 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via preparative TLC eluted withDCM/MeOH 95:5. Re-purification was performed via preparative TLC elutedwith DCM/MeOH 95:5 to give desired product as a white solid (4.9 mg,3.3%). LCMS-Method 2 (200 nm): RT=5.17 min, 100% purity, [M+H]=398.26.¹H NMR (300 MHz, Methanol-d₄) δ 8.12 (s, 1H), 7.55 (d, J=7.9 Hz, 2H),7.37-7.21 (m, 3H), 7.11-6.96 (m, 4H), 6.68 (ddd, J=8.6, 5.5, 1.3 Hz,2H), 4.44 (s, 2H), 4.34 (tt, J=8.4, 3.6 Hz, 1H), 2.06-1.75 (m, 4H),1.66-1.28 (m, 6H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline (O18). Tothe solution of 2-(4-propoxyphenyl)aniline (100 mg, 0.44 mmol) andtert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (152 mg,0.49 mmol) in DMF (1.0 mL) sodium carbonate (140 mg, 1.32 mmol) wasadded. The reaction mixture was stirred overnight at 80° C. After thattime reaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 1:0→98:2. Re-purification was performed via preparative TLCeluted with DCM/MeOH 95:5 to give desired product as a white solid (34.4mg, 21.9%). LCMS-Method 2 (200 nm): RT=4.58 min, 100% purity,[M+H]=358.25. ¹H NMR (300 MHz, Methanol-d₄) δ 8.09 (s, 1H), 7.53 (d,J=7.8 Hz, 2H), 7.36-7.25 (m, 2H), 7.20 (dd, J=8.4, 1.5 Hz, 1H),7.10-6.89 (m, 4H), 6.66 (t, J=7.3 Hz, 2H), 4.37 (s, 2H), 3.90 (t, J=6.5Hz, 2H), 1.77 (dtd, J=13.8, 7.4, 6.4 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline(O19). To the solution of 2-[4-(propan-2-yloxy)phenyl]aniline (100 mg,0.44 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (152 mg, 0.49 mmol) inDMF (1.0 mL) sodium carbonate (140 mg, 1.32 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 1:0→99:1. Re-purification was performed via preparative TLCeluted with DCM/MeOH 95:5 to give desired product as a white solid (24.3mg, 15.5%). LCMS-Method 4 (200 nm): RT=2.42 min, 97.3% purity,[M+H]=358.26. ¹H NMR (300 MHz, Methanol-d₄) δ 8.10 (s, 1H), 7.54 (d,J=7.9 Hz, 2H), 7.37-7.26 (m, 2H), 7.21 (dd, J=8.4, 1.5 Hz, 1H),7.10-6.91 (m, 4H), 6.66 (t, J=7.3 Hz, 2H), 4.57 (hept, J=12.0, 6.0 Hz,1H), 4.39 (s, 2H), 1.31 (d, J=6.0 Hz, 6H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline(O20). To the solution of 2-(4-methoxyphenyl)-3-methylaniline (100 mg,0.47 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (162 mg, 0.52 mmol) inDMF (1.0 mL) sodium carbonate (149 mg, 1.41 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 1:0→97:3. Re-purification was performed via preparative TLCeluted with DCM/MeOH 9:1 to give desired product as a white solid (40.7mg, 25.3%). LCMS (LCMS-Method 4, 205 nm): RT=2.14 min, 98.9% purity,[M+H]=344.27. ¹H NMR (300 MHz, DMSO-d₆) δ 12.33 (d, J=11.8 Hz, 1H), 8.14(s, 1H), 7.57-7.36 (m, 2H), 7.18-7.05 (m, 5H), 6.93 (t, J=7.8 Hz, 1H),6.54-6.38 (m, 2H), 4.44 (d, J=17.8 Hz, 1H), 4.34 (d, J=5.1 Hz, 2H), 3.81(s, 3H), 1.88 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline(O21). To the solution of 2-(3,4-dimethoxyphenyl)-3-methylaniline (100mg, 0.41 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (142 mg, 0.46 mmol) inDMF (1.0 mL) sodium carbonate (131 mg, 1.23 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 1:0→97:3. Re-purification was performed via preparative TLCeluted with DCM/MeOH 95:5 to give desired product as a white solid (47.5mg, 31%). LCMS (LCMS-Method 4, 205 nm): RT=1.99 min, 97.3% purity,[M+H]=374.27. ¹H NMR (300 MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.14 (s, 1H),7.52 (s, 1H), 7.41 (s, 1H), 7.10 (t, J=7.8 Hz, 2H), 6.93 (t, J=7.8 Hz,1H), 6.79-6.71 (m, 2H), 6.47 (dd, J=15.8, 7.8 Hz, 2H), 4.55 (s, 1H),4.34 (d, J=6.0 Hz, 2H), 3.79 (d, J=9.0 Hz, 6H), 1.92 (s, 3H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline(O22). To the solution of 2-(4-chlorophenyl)-3-fluoroaniline (100 mg,0.45 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (156 mg, 0.50 mmol) inDMF (1.0 mL) sodium carbonate (143 mg, 1.35 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 1:0→97:3. Re-purification was performed via preparative TLCeluted with DCM/MeOH 95:5 to give desired product as a white solid (40.6mg, 25.6%). LCMS (LCMS-Method 4, 200 nm): RT=2.29 min, 94.2% purity,[M+H]=344.27. ¹H NMR (300 MHz, DMSO-d₆) δ 12.33 (d, J=17.3 Hz, 1H), 8.15(d, J=4.1 Hz, 1H), 7.58 (dd, J=8.8, 7.0 Hz, 3H), 7.50-7.36 (m, 3H),7.20-7.10 (m, 1H), 7.05 (td, J=8.3, 6.8 Hz, 1H), 6.46-6.34 (m, 2H), 5.48(dt, J=16.2, 6.0 Hz, 1H), 4.38 (t, J=6.0 Hz, 2H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline(O23). To the solution of 2-(3,4-dimethoxyphenyl)-3-fluoroaniline (100mg, 0.40 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (140 mg, 0.45 mmol) inDMF (1.0 mL) sodium carbonate (129 mg, 1.21 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 1:0→97:3. Re-purification was performed via preparative TLCeluted with DCM/MeOH 9:1 to give desired product as a white solid (29.3mg, 19.2%). LCMS (LCMS-Method 4, 200 nm): RT=1.92 min, 90.1% purity,[M+H]=378.23. ¹H NMR (300 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.16 (s, 1H),7.50 (s, 2H), 7.21-6.98 (m, 3H), 6.93-6.85 (m, 2H), 6.45-6.37 (m, 2H),5.27 (s, 1H), 4.39 (d, J=6.0 Hz, 2H), 3.80 (d, J=7.1 Hz, 6H).

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline(O24). To the solution of 3-fluoro-2-(4-fluorophenyl)aniline (100 mg,0.49 mmol) and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (168 mg, 0.54 mmol) inDMF (1.0 mL) sodium carbonate (155 mg, 1.46 mmol) was added. Thereaction mixture was stirred overnight at 80° C. After that timereaction mixture was cooled down to RT and filtered through celite.Celite pad was washed with MeOH. Filtrate was evaporated to provide thecrude product, which was purified via column chromatography usingDCM/MeOH 1:0→97:3. Re-purification was performed via preparative TLCeluted with DCM/MeOH 9:1 to give desired product as a white solid (29.3mg, 19.2%). LCMS (LCMS-Method 4, 205 nm): RT=2.12 min, 96.6% purity,[M+H]=336.23. ¹H NMR (300 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.15 (s, 1H),7.55 (s, 1H), 7.45-7.32 (m, 5H), 7.15 (s, 1H), 7.10-6.99 (m, 1H),6.46-6.36 (m, 2H), 5.37 (s, 1H), 4.39 (d, J=6.0 Hz, 2H).

Synthesis Method Q

N-[(1H-1,3-benzodiazol-5-yl)methyl]-4-fluorobenzene-1-sulfonamide (P1)(1H-1,3-benzodiazol-5-yl)methanamine dihydrochloride (0.25 g, 1.15 mmol)was dissolved in pyridine (7 mL) and stirred at room temperature over 30min. Then 4-fluorophenylsulfonyl chloride (0.21 g, 1.08 mmol), was addedand reaction mixture was heated to 70° C. and stirred overnight. Themixture was quenched with 10 mL of 20% aqueous solution of sodiumhydroxide and stirred at 70° C. for another night. Layers were separatedand Pyridine was evaporated in vacuo. Crude product was purified viacolumn chromatography using MeOH in DCM (0-3%) as eluent. Fractionscontaining the title compound were combined and concentrated (55 mg,19%). LCMS-Method 1 (200 nm): RT=5.81 min, 93.2% purity, [M+ACN]=347.27.¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s, 1H), 8.04-7.66 (m, 2H), 7.56-7.31(m, 4H), 7.05 (d, J=8.4 Hz, 1H), 4.10 (s, 2H).

Synthesis Method R

[(1H-1,3-benzodiazol-5-yl)methyl][(4-fluorophenyl)(methyl)oxo-λ⁶-sulfanylidene]amine(Q1) (4-fluorophenyl)(imino)methyl-λ⁶-sulfanone (250 mg, 1.5 mmol) andpotassium hydroxide (234 mg, 2.18 mmol) in DMSO (13.0 mL) were stirredat 50° C. over 1 h. After this time reaction was cooled to roomtemperature and tert-butyl5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (650 mg, 2.10 mmol)was added. Reaction was stirred overnight, and after this time water (50mL) was added and extracted with DCM (5×30 mL). Combined organic layerswere dried over sodium sulfate, filtered, evaporated to provide thesolution of crude product in DMSO, which was purified preparative HPLCmethod to give title compound as colorless oil. (26 mg, 5%) LCMS-Method1 (200 nm): RT=5.72 min, 96.3% purity, [M+H]=304.15. ¹H NMR (300 MHz,DMSO-d₆) δ 8.14 (s, 1H), 8.03-7.91 (m, 2H), 7.54 (s, 1H), 7.51-7.42 (m,3H), 7.12 (dd, J=8.3, 1.6 Hz, 1H), 4.15 (d, J=14.4 Hz, 1H), 3.98 (d,J=14.5 Hz, 1H), 3.25 (s, 3H).

Analytical Methods

NMR

The ¹H NMR-Spectra (300 MHz) were recorded at a BRUKER FOURIER 300. Thesolvent was DMSO-D₆, unless otherwise specified. Chemical shifts areexpressed as parts per million (ppm) downfiled from tetramethylsilan.Splitting patterns have been designated as follows: s (singulet), d(doublet), dd (doublet of doublet), t (triplet), m (multiplet) and br(broad signal).

HPLC-MS

LCMS-Method 1

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO,internal column no. 002

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 0.5 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 14 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 95 50.5 2.0 95 5 0.5 9.5 20 80 0.5 10.5 20 80 0.5 12.0 95 5 0.5 14.0 95 50.5

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 2

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO,internal column no. 002

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 0.5 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 12 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 80 200.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 80 20 0.512.0 80 20 0.5

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 3

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A, column no.OOB-4496-EO, internal column no. 019

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 1.0 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 7 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 95 51.0 1.0 95 5 1.0 4.75 20 80 1.0 5.25 20 80 1.0 6.0 95 5 1.0 7.0 95 5 1.0

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH        MS conditions: —Mass range: 100-1000 m/z    -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 4

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A, column no.OOB-4496-EO, internal column no. 019

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 1.0 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 6 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 80 201.0 3.35 20 80 1.0 3.75 20 80 1.0 3.9 5 95 1.0 4.75 5 95 1.0 5.0 80 201.0 6.0 80 20 1.0

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 5

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A, column no.OOB-4496-EO, internal column no. 019

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 1.0 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 7 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 80 201.0 2.0 20 80 1.0 2.35 20 80 1.0 2.45 5 95 1.0 4.25 5 95 1.0 5.0 80 201.0 7.0 80 20 1.0

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

HPLC-Method 6

Apparatus: HPLC-MERCK CHROMASTER with gradient pump and DAD detector

Column: XBridge C18 3.5μ (4.6×150 mm), column no. 186003034, internalcolumn no. 009

Reagents:

-   -   Methanol for HPLC Ultra Gradient HPLC Grade, Baker    -   Boric acid ≥99.5%, Sigma-Aldrich    -   Sodium hydroxide analytical grade, Eurochem BGD    -   purified water for HPLC

HPLC conditions:

-   -   Wavelength: 210.0 nm±4.0 nm    -   Flow: 0.5 mL/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 5 μL    -   Analysis time: 30 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [mL/min] 0.0 50 500.5 22.0 5 95 0.5 25.0 5 95 0.5 27.0 50 50 0.5 30.0 50 50 0.5

Mobile phase A:

-   -   Borate buffer c=5 mM, pH=9.6    -   Preparation: 0.618 g of boric acid placed in 2 L volumetric        flask were dissolved in 1.5 L purified water. pH value was        adjusted to 9.6 using 1M solution of NaOH (6 mL).    -   Finally, solution was diluted to the mark using purified water.

Mobile phase B:

1 L MeOH with the analogous amount of 1M NaOH as in phase A (3 mL).

Solution for syringe washing: acetonitrile

LCMS-Method 7

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO,internal column no. 002

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 0.5 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 12 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 60 400.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 60 40 0.512.0 60 40 0.5

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 8

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO,internal column no. 002

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 0.5 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 28 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 95 50.5 4.0 95 5 0.5 19.0 20 80 0.5 21.0 20 80 0.5 24.0 95 5 0.5 28.0 95 50.5

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 9

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Kinetex XB-C18 2.6 μm (4.6×50 mm), 100A, column no. OOB-4496-EO,internal column no. 019

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 1.0 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 7 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 100 01.0 1.0 95 5 1.0 4.0 80 20 1.0 4.75 20 80 1.0 5.25 20 80 1.0 6.0 95 51.0 7.0 100 0 1.0

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 10

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO,internal column no. 002

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 0.5 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 12 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 70 300.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 70 30 0.512.0 70 30 0.5

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 11

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A, column no.OOB-4496-EO, internal column no. 019

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 1.0 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 6 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 30 701.0 3.35 20 80 1.0 3.75 20 80 1.0 3.9 5 95 1.0 4.75 5 95 1.0 5.0 30 701.0 6.0 30 70 1.0

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

LCMS-Method 12

Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/ThermoScientific MSQ Plus

Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO,internal column no. 002

Reagents: —Formic acid ≥98%, Sigma-Aldrich

-   -   Acetonitrile for HPLC UV/gradient grade, Baker    -   μQ-water for LCMS

HPLC conditions: —Wavelength range: (190-340) nm±4 nm

-   -   Flow: 0.5 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 2.0 μl    -   Analysis time: 14 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 100 00.5 2.0 95 5 0.5 8.0 80 20 0.5 9.5 20 80 0.5 10.5 20 80 0.5 12.0 95 50.5 14.0 100 0 0.5

-   -   Mobile phase A: 0.1% v/v water solution of formic acid    -   Mobile phase B: 0.1% v/v acetonitrile solution of formic acid    -   Solution for syringe washing: 20% MeOH

MS conditions: —Mass range: 100-1000 m/z

-   -   Ionization: alternate    -   Scan speed: 12 000 amu/sec

UPLC-MS

Apparatus: Shimadzu LCMS-2020 Single Quadrupole Liquid ChromatographMass Spectrometer

Column: Acquity UPLC 1.8 μm C18 (2.1×50 mm), 100 Å, column no.186003532, internal column no. Pur CC-MS001

Reagents:

-   -   Formic acid ≥98%, Sigma-Aldrich,    -   Acetonitrile for HPLC UV/gradient grade, Baker,    -   purified water for HPLC.

UPLC conditions:

-   -   Wavelength: 254 nm and 280 nm    -   Flow: 0.5 ml/min    -   Column temperature: 25° C.    -   Autosampler temperature: 20° C.    -   Injection volume: 3 μl    -   Analysis time: 6.0 min    -   Elution: gradient

Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.01 95 50.5 4.00 5 95 0.5 5.00 5 95 0.5 5.20 95 5 0.5 6.00 95 5 0.5

Mobile phase A:

0.1% v/v water solution of formic acid

-   -   Mobile phase B:

0.1% v/v acetonitrile solution of formic acid

Solution for syringe washing:

100% acetonitrile

MS conditions:

-   -   Mass range: 50-1000 m/z    -   Ionization: alternate    -   Scan speed: 7500 u/sec

Activity Screening

Glutaminyl Cyclase, Assay Determination of IC50 Values and Calculationof Ki Values

10 mM compound stock solutions were prepared in DMSO. For IC50determination compound stocks were serially diluted (1:3) in DMSO.

All measurements were performed with an EnSpire Perkin Elmer multimodereader using glutaminyl-7-amino-4-methylcoumarin (H-Gln-AMC) assubstrate and recombinant pyroglutamyl aminopeptidase (pGAP) asauxiliary enzyme. Reactions were carried out at ambient temperature inblack 96-well half area microplates. Each sample consisted of 1 μl testcompound solution or solvent (DMSO) and 49 μl QC appropriately dilutedin assay buffer (50 mM Tris/HCl, pH 8.0 or 50 mM MES buffer, pH=6.0).After a 10 min preincubation at ambient temperature the enzyme reactionwas started by adding 50 μl of Gln-AMC-substrate/pGAP mixture in assaybuffer. Final substrate concentrations were 50 and 200 μM formeasurement at pH 8.0 or 6.0, respectively. Release of flourogenic AMCwere recorded at excitation/emission wavelengths of 380/460 nm. Initialvelocity of the enzyme reaction was calculated by linear regression ofthe first 10 data points using the Enspire Manager software. Finalevaluation and calculation of IC50s were performed using GraphPad Prismsoftware. IC50 values were calculated from normalized data (QC activitywithout inhibitor=100%) by nonlinear regression according to a4-parameter logistic equation.

Ki-values were calculated according to the following formula:Ki=IC₅₀/(1+[S]/Km), where: [S] reflects to the concentration ofsubstrate in the assay (200 μM for pH 6.0, 50 μM for pH 8.0) and Km isthe respective Michaelis-Menten constant (390 μM at pH 6.0, 62 μM at pH8.0).

MALDI-TOF Mass Spectrometry

Matrix-assisted laser desorption/ionization mass spectrometry wascarried out using the Hewlett-Packard G2025 LD-TOF System with a lineartime of flight analyzer. The instrument was equipped with a 337 nmnitrogen laser, a potential acceleration source (5 kV) and a 1.0 mflight tube. Detector operation was in the positive-ion mode and signalsare recorded and filtered using LeCroy 9350M digital storageoscilloscope linked to a personal computer. Samples (5 μl) were mixedwith equal volumes of the matrix solution. For matrix solution DHAP/DAHCwas used, prepared by solving 30 mg 2″,6″-dihydroxyacetophenone(Aldrich) and 44 mg diammonium hydrogen citrate (Fluka) in 1 mlacetonitrile/0.1% TFA in water (1/1, v/v). A small volume (≈1 μl) of thematrix-analyte-mixture was transferred to a probe tip and immediatelyevaporated in a vacuum chamber (Hewlett-Packard G2024A sample prepaccessory) to ensure rapid and homogeneous sample crystallization.

For long-term testing of Glu′-cyclization, Aβ-derived peptides wereincubated in 100 μl 0.1 M sodium acetate buffer, pH 5.2 or 0.1 MBis-Tris buffer, pH 6.5 at 30° C. Peptides were applied in 0.5 mM[Aβ(3-11)a] or 0.15 mM [Aβ(3-21)a] concentrations, and 0.2 U QC is addedall 24 hours. In case of Aβ(3-21)a, the assays contained 1% DMSO. Atdifferent times, samples are removed from the assay tube, peptidesextracted using ZipTips (Millipore) according to the manufacturer'srecommendations, mixed with matrix solution (1:1 v/v) and subsequentlythe mass spectra recorded. Negative controls either contain no QC orheat deactivated enzyme. For the inhibitor studies the samplecomposition was the same as described above, with exception of theinhibitory compound added (5 mM or 2 mM of a test compound of theinvention).

Compounds and combinations of the invention may have the advantage thatthey are, for example, more potent, more selective, have fewerside-effects, have better formulation and stability properties, havebetter pharmacokinetic properties, be more bioavailable, be able tocross blood brain barrier and are more effective in the brain ofmammals, are more compatible or effective in combination with otherdrugs or be more readily synthesized than other compounds of the priorart.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer, step, group of integers or group of steps but notto the exclusion of any other integer, step, group of integers or groupof steps.

All patents and patent applications mentioned throughout thespecification of the present invention are herein incorporated in theirentirety by reference.

The invention embraces all combinations of preferred and more preferredgroups and embodiments of groups recited above.

1: A compound of formula I:A-B-D-E  (I) or a pharmaceutically acceptable salt, solvate or polymorphthereof, including all tautomers and stereoisomers thereof, wherein: Ais selected from monocyclic and bicyclic heteroaryl selected from

B is selected from alkyl, heteroalkyl, alkyl-amino, aryl, heteroaryl,cycloalkyl, heterocyclyl and alkylene, wherein said groups mayindependently be substituted by alkyl; D is selected from aryl-amino,heteroaryl-amino, cycloalkyl-amino, heterocyclyl, heterocyclyl-amino,sulfonamide, sulfoximine and sulfamoyl, wherein said aryl, heteroaryl,cycloalkyl and heterocyclyl groups may independently be substituted withone or more substituents; E is selected from aryl, heteroaryl,cycloalkyl, heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl andheterocyclyl groups may independently be substituted with one or moresubstituents; heteroaryl, cycloalkyl and heterocyclyl groups mayindependently be substituted with one or more substituents; with theprovisos that i) when B is alkyl or heteroalkyl, then D may not besulfonamide; and ii) the compound of formula (I) is not a compoundselected from:

2: The compound according to claim 1, wherein A is a monocyclicheteroaryl selected from thiadiazolyl, thiazolyl and triazolyl, andwherein said monocyclic heteroaryl is substituted by amino or methyl; orwherein A is a bicyclic heteroaryl selected from benzimidazole andimidazopyridine. 3: The compound according to claim 1, wherein A isselected from

4: The compound according to claim 1, wherein B is selected fromC₃₋₅-heteroalkyl, phenyl, C₅-C₆-heterocyclyl and C₁₋₅ alkylene, whereinsaid C₁₋₅ alkylene group may independently be substituted by alkyl. 5:The compound according to claim 1, wherein B is selected from

wherein X₁ is alkyl, N, O or S, preferably methyl or S; and n is 1 or 2;

wherein o is 0 or 1; and p is 0 or 1; and

wherein R₁ is hydrogen or alkyl and q is 0, 1 or
 2. 6: The compoundaccording to claim 1, wherein D is a group selected from

wherein wherein R is absent or is hydrogen; or R forms together with thenitrogen atom, to which it is attached a heterocyclic ring of group B;R₂ is hydrogen, alkyl or cycloalkyl; Y₁, Y₂, Y₃ and Y₄ are independentlyselected from CH, N, S and O; Y₄ is optionally substituted with alkyl orhalogen. 7: The compound according to claim 1, wherein E is

wherein Y₅ is C and Y₆-Y₁₀ are independently selected from CH, N or O,and R₃, R₄, R₅, R₆, and R₇ are independently selected from hydrogen,halogen, alkyl, O-alkyl, O-phenyl and O-cycloalkyl. 8: The compoundaccording to claim 1, which is a compound of formula (IIa) or formula(IIb):

wherein Z is selected from CH and N; X₁ is selected from alkyl, N, O, S;n is 1 or 2; Y₁ to Y₄ and Y₆ to Y₁₀ are independently selected from CH,N, S and O; Y₅ is C; R₅ is selected from halogen, alkyl and O-alkyl; andR₆ is selected from hydrogen, alkyl and O-alkyl. 9: The compoundaccording to claim 1, which is a compound of formula (IIIa) or formula(IIIb):

wherein X₁ is selected from alkyl, N, O, S; n is 1 or 2; Y₁ to Y₄ and Y₆to Y₁₀ are independently selected from CH, N, S and O; Y₅ is C; R₅ isselected from halogen, alkyl and O-alkyl; and R₆ is selected fromhydrogen, alkyl and O-alkyl. 10: The compound according to claim 1,which is a compound of formula (IVa) or formula (IVb):

wherein Z is selected from CH and N; o is 0 or 1; p is 0 or 1; Y₁ to Y₄and Y₆ to Y₁₀ are independently selected from CH, N, S and O; Y₅ is C;R₅ is selected from halogen, alkyl, O-alkyl and O-phenyl; and R₆ isselected from hydrogen, alkyl and O-alkyl. 11: The compound accordingclaim 1, which is a compound of formula (Va) or formula (Vb):

wherein o is 0 or 1; p is 0 or 1; Y₁ to Y₄ and Y₆ to Y₁₀ areindependently selected from CH, N, S and O; Y₅ is C; R₅ is selected fromhalogen, alkyl, O-alkyl and O-phenyl; and R₆ is selected from hydrogen,alkyl and O-alkyl. 12: The compound according to claim 1, which is acompound of formula (VI):

wherein Z is selected from CH and N; X₁ is selected from alkyl, N, O, S;n is 1 or 2; R₅ is selected from halogen, alkyl and O-alkyl; and R₆ isselected from hydrogen, alkyl and O-alkyl. 13: The compound according toclaim 1, which is a compound of formula (VII):

wherein Z is selected from CH and N; X₁ is selected from alkyl, N, O, S;n is 1 or 2; R₂ is selected from alkyl and cycloalkyl; R₅ is selectedfrom halogen, alkyl and O-alkyl; and R₆ is selected from hydrogen, alkyland O-alkyl. 14: The compound according to claim 1, which is a compoundof formula (VIII):

wherein X₁ is selected from alkyl, N, O, S; n is 1 or 2; R₅ is selectedfrom halogen, alkyl and O-alkyl; and R₆ is selected from hydrogen, alkyland O-alkyl. 15: The compound according to claim 1, which is a compoundof formula (IX):

wherein X₁ is selected from alkyl, N, O, S; n is 1 or 2; R₂ is selectedfrom alkyl and cycloalkyl; R₅ is selected from halogen, alkyl andO-alkyl; and R₆ is selected from hydrogen, alkyl and O-alkyl. 16: Thecompound according to claim 1, which is a compound of formula (X):

wherein o is 0 or 1; p is 0 or 1; R₅ is selected from halogen, alkyl andO-alkyl; and R₆ is selected from hydrogen, alkyl and O-alkyl. 17: Thecompound according to claim 1, which is a compound of formula (XI):

wherein o is 0 or 1; p is 0 or 1; R₂ is selected from alkyl andcycloalkyl; R₅ is selected from halogen, alkyl and O-alkyl; and R₆ isselected from hydrogen, alkyl and O-alkyl. 18: The compound according toclaim 6, wherein NR is represented by

19: The compound according to claim 1, which is a compound of formula(XIIa) or formula (XIIb):

wherein Z is selected from CH and N; Y₁ to Y₄ and Y₆ to Y₁₀ areindependently selected from CH, N, S and O; Y₅ is C; R₅ is selected fromhalogen, alkyl and O-alkyl; and R₆ is selected from hydrogen, alkyl andO-alkyl. 20: The compound according to claim 1, which is a compound offormula (XIII):

wherein Z is selected from CH and N; R₅ is selected from halogen, alkyland O-alkyl; and R₆ is selected from hydrogen, alkyl and O-alkyl. 21:The compound according claim 1, which is a compound of formula (XIV):

wherein R₅ is selected from halogen, alkyl and O-alkyl; and R₆ isselected from hydrogen, alkyl and O-alkyl. 22: The compound according toclaim 1, which is a compound of formula (XVa) or formula (XVb):

wherein Y₁ to Y₄ and Y₆ to Y₁₀ are independently selected from CH, N, Sand O; Y₅ is C; Y₄ is optionally substituted with alkyl or halogen; R₅is selected from halogen, alkyl, O-alkyl, O-phenyl and O-cycloalkyl; andR₆ is selected from hydrogen, alkyl and O-alkyl. 23: The compoundaccording to claim 1, which is a compound of formula (XVI):

wherein R₅ is selected from halogen, alkyl and O-alkyl; and R₆ isselected from hydrogen, alkyl and O-alkyl. 24: The compound according toclaim 1, which is a compound of formula (XVII):

wherein R₂ is selected from alkyl and cycloalkyl; R₅ is selected fromhalogen, alkyl and O-alkyl; and R₆ is selected from hydrogen, alkyl andO-alkyl. 25: The compound according to claim 1, which is a compound offormula (XVIII):

wherein X₁ is selected from alkyl, N, O, S; n is 1 or 2; R₅ is selectedfrom halogen, alkyl and O-alkyl; and R₆ is selected from hydrogen, alkyland O-alkyl.
 26. (canceled) 27: The compound according to claim 1, whichis a compound selected from:5-[3-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine;5-{[2-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine;5-{[2-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine;4′-fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1′-biphenyl]-2-amine;3′,4′-dimethoxy-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1′-biphenyl]-2-amine;5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine;5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine;5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine;N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine;N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine;N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine;N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine;N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine;5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine;5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine;5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine;4′-fluoro-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1′-biphenyl]-2-amine;3′,4′-dimethoxy-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1′-biphenyl]-2-amine;N-[2-(4-methoxyphenyl)phenyl]-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline;2-(4-methoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine;2-(4-fluorophenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine;4-(4-methyl-4H-1,2,4-triazol-3-yl)-N-[2-(4-phenoxyphenyl)phenyl]aniline;3-(3,4-dimethoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine;N-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]-4-fluorobenzene-1-sulfonamide;N-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]ethyl}-4-fluorobenzene-1-sulfonamide;5-(3-{[(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine;4-fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]benzene-1-sulfonamide;4-fluoro-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl}benzene-1-sulfonamide;[(3,4-dimethoxyphenyl)sulfamoyl]({2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl})amine;N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide;N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide;5-(1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine;5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-amine;5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-amine;1-(4-fluorobenzenesulfonyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine;N-[(1H-1,3-benzodiazol-5-yl)methyl]-4′-fluoro-[1,1′-biphenyl]-2-amine;N-[(1H-1,3-benzodiazol-5-yl)methyl]-3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline;N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline;N-[(1H-1,3-benzodiazol-5-yl)methyl]-4-fluorobenzene-1-sulfonamide; and[(1H-1,3-benzodiazol-5-yl)methyl][(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amine;or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers.
 28. (canceled) 29: Apharmaceutical composition comprising a compound according to claim 1together with a therapeutically acceptable diluent. 30: Thepharmaceutical composition of claim 29, which comprises additionally atleast one compound, selected from the group consisting ofneuroprotectants, antiparkinsonian drugs, amyloid protein depositioninhibitors, beta amyloid synthesis inhibitors, antidepressants,anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.31: The pharmaceutical composition of claim 29, which comprisesadditionally at least one compound, selected from the group consistingof PEP-inhibitors, LiCl, inhibitors of inhibitors of DP IV or DP IV-likeenzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers,inhibitors of beta secretases, inhibitors of gamma secretases,inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4(PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDAreceptor antagonists, sigma-1 receptor inhibitors, histamine H3antagonists, immunomodulatory agents, immunosuppressive agents or anagent selected from the group consisting of antegren (natalizumab),Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD271, adapalene), BAY 361677 (interleukin-4),matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) andSAIK-MS. 32-34. (canceled) 35: A method of treatment or prevention of adisease selected from the group consisting of Kennedy's disease, ulcerdisease, duodenal cancer with or without Helicobacter pylori infections,colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with orwithout Helicobacter pylori infections, pathogenic psychotic conditions,schizophrenia, infertility, neoplasia, inflammatory host responses,cancer, malign metastasis, melanoma, psoriasis, impaired humoral andcell-mediated immune responses, leukocyte adhesion and migrationprocesses in the endothelium, impaired food intake, impairedsleep-wakefulness, impaired homeostatic regulation of energy metabolism,impaired autonomic function, impaired hormonal balance or impairedregulation of body fluids, multiple sclerosis, the Guillain-Barrésyndrome and chronic inflammatory demyelinizing polyradiculoneuropathy,which comprises administering to a subject an effective amount of apharmaceutical composition according to claim
 29. 36: A method oftreatment or prevention of a disease selected from the group consistingof mild cognitive impairment, Alzheimer's disease, Familial BritishDementia, Familial Danish Dementia, neurodegeneration in Down Syndromeand Huntington's disease, which comprises administering to a subject aneffective amount of a pharmaceutical composition according to claim 29.37: A method of treatment or prevention of a disease selected from thegroup consisting of rheumatoid arthritis, atherosclerosis, pancreatitisand restenosis, which comprises administering to a subject an effectiveamount of a pharmaceutical composition according to claim 29.